Pyrrolidine-2, 5-dione derivatives, pharmaceutical compositions and methods for use as ido1 inhibitors

ABSTRACT

The present invention relates to compound of Formula I 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable enantiomers, salts, solvates or prodrugs thereof. The invention further relates to the use of the compounds of Formula I as IDO1 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer and endometriosis. The invention also relates to a process for manufacturing compounds of Formula I.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application No. 61/996,976, filed May 15, 2014.

FIELD OF INVENTION

The present invention relates to pyrrolidine-2,5-dione derivatives,including pharmaceutically acceptable enantiomers, salts, solvates andprodrugs thereof. Compounds of the invention are inhibitors of IDO1(indoleamine 2,3-dioxygenase-1) and are useful as therapeutic compounds,particularly in the treatment and/or prevention of cancers.

BACKGROUND OF INVENTION

Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric,heme-containing enzyme that catalyzes the first and rate limiting stepof L-tryptophan (Trp) catabolism along the kynurenine pathway, leadingto the production of N-formylkynurenine. 95% of Trp is metabolizedthrough this kynurenine pathway. The kynurenine pathway (KYN) initiatesthe production of neuroactive and immunoregulatory metabolites,collectively known as kynurenines and provides precursors thatsupplement dietary niacin for the biosynthesis of NAD+ and NADP+.

By locally depleting tryptophan and increasing kynurenines, IDO1expressed by antigen presenting cells (APCs) such as dendritic cells(plasmacystoid DCs in tumor draining lymph nodes) can greatly affectT-cell proliferation and survival and activate regulatory T cellsthereby reducing proinflammatory responses. IDO1 can thus provide“immune privilege” to tissues subject to chronic inflammations such asinfectious and allergic diseases, transplantation and cancer. Becausesuch tolerogenic responses can be expected to operate in a variety ofphysiopathological conditions, tryptophan metabolism and kynurenineproduction through IDO1 might represent a crucial interface between theimmune and nervous system. Expression of IDO1 is upregulated byproinflammatory cytokines and can be detected in a variety of tissues,including placenta, spleen, thymus, lung, digestive tract, and centralnervous system (reviewed in Munn et al. Trends Immunol, 2013, 34,137-43).

IDO1 has emerged as a promising molecular target of new therapeuticagents for treating cancer as well as other diseases characterized bythe reduction of local Trp levels and/or to imbalances in the level ofcytotoxic metabolites produced by the kynurenine pathway (reviewed inMunn et al. Trends Immunol, 2013, 34, 137-43). Indeed inhibition of IDO1activity as a therapeutic strategy has been tested in preclinical modelsof many diseases, with the most widely used IDO1 inhibitor, thetryptophan analogue L-1-methyltryptophan (L-1MT). Treatment with L-1MT,alone or in combination with other agents, attenuated disease severityin animal models of arthritis, ischemia-reperfusion injury, endotoxinshock, human immunodeficiency virus (HIV)/simian immunodeficiency virus(SIV) infection, airway inflammation, and cancer (Uyttenhove et al., NatMed, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210, 7,1389-1402), among others. For cancer, IDO1 induction has been observedin vivo during rejection of allogeneic tumors, indicating a possiblerole for this enzyme in the tumor rejection process (Uyttenhove et al.,Nat Med, 2003, 9, 10, 1269-1274; Holmgaard et al., J Exp Med, 2013, 210,7, 1389-1402). Cervical carcinoma cells (or HeLa cells) co-cultured withperipheral blood lymphocytes (PBLs) acquire an immuno-inhibitoryphenotype through up-regulation of IDO1 activity. A reduction in PBLproliferation upon treatment with interleukin-2 (IL2) was believed toresult from IDO1 released by the tumor cells in response to gammainterferon (IFN)-g (γ) secretion by the PBLs. IDO1 activity in tumorcells may thus serve to impair anti-tumor responses, a process in whichIFNg plays a central role. Further evidence for a tumoral immuneresistance mechanism based on tryptophan degradation by IDO1 comes fromthe observation that most human tumors constitutively express IDO1, andthat expression of IDO1 by immunogenic mouse tumor cells prevents theirrejection (reviewed in Munn et al., Front Biosci, 2012, 4, 734-45;Godin-Ethier et al. Clin Cancer Res 2011, 17, 6985-6991; Johnson et al.Immunol Invest 2012, 41, 6-7, 765-797). This effect is accompanied by alack of accumulation of specific T cells at the tumor site and can bepartly reverted by systemic treatment of mice with an inhibitor of IDO1,in the absence of noticeable toxicity (Holmgaard et al., J Exp Med,2013, 210, 7, 1389-1402).

IDO1 expression has been demonstrated by immunohistochemistry in a widespectrum of cancer patients. IDO1 mRNA, protein or modification of theratio of tryptophan and kynurenine in the blood have been detected inpatients with malignant melanoma, acute myelogenous leukemia,pancreatic, colorectal, prostate, cervical, brain, endometrial andovarian cancers amongst others. In several malignancies, the presence ofIDO1 is an independent predictor of a worse clinical outcome (reviewedin Munn et al., Front Biosci, 2012, 4, 734-45)

Although the potential of the IDO1 inhibitors as pharmaceutical agentshas generated a significant interest, the initial inhibitors wereidentified by modification of Trp but not the discovery of moleculesbearing novel structural skeleton. In the early 2000's, the best IDO1inhibitors were mainly comprised of competitive Trp derivatives (likeL-1-MT) and noncompetitive carbolines, which displayed affinities in themicromolar range. Since 2006, some potent nanomolar IDO1 inhibitors withnovel structural skeleton have been discovered by high throughputscreening, computational screening or natural product isolation andoptimization of the core pharmacophores in the structures. Many of theseIDO1 inhibitors possess low micromolar activities or limitedpharmacokinetics. Two IDO1 inhibitors are currently being tested inphase I/II clinical trials for the treatment of relapsed or refractorysolid tumors (reviewed in Dolu{hacek over (s)}ić et al., Expert OpinTher Pat. 2013, 23, 1367-81).

In parallel, the importance of awakening and solidifying tumor immunesurveillance is now widely accepted as an important aspect ofanti-cancer therapy (Motz et al., Immunity, 2013, 39, 1, 61-73).Immunoscoring of infiltrating T cell subsets is under development asbiomarker approach and will allow to determine the patients'responsiveness to treatment (Galon et al., J Transl Med, 2012, 10, 1).Hence, it is still of major interest to find new potent IDO1 inhibitors.

Therefore, there is a need for new IDO1 inhibitors with improvedefficacy for cancer treatment and/or prevention.

SUMMARY OF THE INVENTION

The compounds, compositions and methods herein help meet the currentneed for IDO1 inhibitors which can be administered to any patientdiagnosed with cancer, or any subject at risk of developing a cancer.

In one aspect, a pharmaceutical composition or a medicament comprising acompound of Formula Ia is provided:

-   -   or a pharmaceutically acceptable enantiomer, salt, solvate or        prodrug thereof, wherein:        -   X^(a) represents —NH— or —CQ²=CQ³-;        -   Q² and Q³ each independently represent H or C1 to C6 alkyl,            preferably Q² and Q³ each independently represent H or            methyl, more preferably Q² and Q³ represent H;        -   R¹ and R² each independently represent H, halo, cyano, C1 to            C6 alkyl or C1 to C6 alkoxy, preferably R¹ and R² each            independently represent H or halo.

In another aspect, a pharmaceutical composition comprising a compound ofFormula Ia is provided:

-   -   or a pharmaceutically acceptable enantiomer, salt, solvate or        prodrug thereof, wherein:        -   X^(a) represents —NH— or —CQ²=CQ³-;        -   Q² and Q³ each independently represent H or C1 to C6 alkyl,            preferably Q² and Q³ each independently represent H or            methyl, more preferably Q² and Q³ represent H;        -   R¹ and R² each independently represent H, halo, cyano, C1 to            C6 alkyl or C1 to C6 alkoxy, preferably R¹ and R² each            independently represent H or halo;    -   and at least one pharmaceutically acceptable carrier.

Also provides is a compound of Formula Ia

-   -   or a pharmaceutically acceptable enantiomer, salt, solvate or        prodrug thereof, wherein:        -   X^(a) represents —NH— or —CQ²=CQ³-;        -   Q² and Q³ each independently represent H or C1 to C6 alkyl,            preferably Q² and Q³ each independently represent H or            methyl, more preferably Q² and Q³ represent H;        -   R¹ and R² each independently represent H, halo, cyano, C1 to            C6 alkyl or C1 to C6 alkoxy, preferably R¹ and R² each            independently represent H or halo.

In one embodiment, the compound of Formula I and/or Formula Ia has adeuterium atom substituted for a hydrogen atom therein, i.e., isoptionally deuterated. In one embodiment, the compound of Formula I isdeuterated at the chiral carbon and may be used to prepare deuteratedcompounds of Formula I′ and/or Formula I″. The compounds describedherein, including those of Formula I, Formula Ia, Formula Ib, Formula I′and Formula I″, and their deuterated counterparts are useful in thetreatment and/or prevention of cancer and endometriosis, and/or for useas IDO1 inhibitor.

Also provided is a compound of Formula Ia′

or a pharmaceutically acceptable enantiomer, salt, solvate or prodrugthereof, wherein:

-   -   X^(a) represents —NH— or —CQ²=CQ³-;    -   Q² and Q³ each independently represent H or C1 to C6 alkyl,        preferably Q² and Q³ each independently represent H or methyl,        more preferably Q² and Q³ represent H;    -   R¹ and R² each independently represent H, halo, cyano, C1 to C6        alkyl or C1 to C6 alkoxy, preferably R¹ and R² each        independently represent H or halo.

In one embodiment, a compound of Formula I and/or Ia is deuterated atthe chiral center, as in the structure of Formula Ia′

or a pharmaceutically acceptable enantiomer, salt, solvate or prodrugthereof, wherein:

-   -   X^(a) represents —NH— or —CQ²=CQ³-;    -   Q² and Q³ each independently represent H or C1 to C6 alkyl,        preferably Q² and Q³ each independently represent H or methyl,        more preferably Q² and Q³ represent H;    -   R¹ and R² each independently represent H, halo, cyano, C1 to C6        alkyl or C1 to C6 alkoxy, preferably R¹ and R² each        independently represent H or halo.

In one embodiments, racemic compounds of Formula I and/or Ia may bedeuterated using the techniques described herein and/or those known toone of skill in the art. Such compounds may be used in a medicament orpharmaceutical composition, and/or production of a deuteratedR-enantiomer and/or a deuterated S-enantiomer. Such a deuteratedenantiomer may itself be used in a medicament or pharmaceuticalcomposition as described herein.

Further, a compound of Formula I′, Formula I″, or a mixture thereof isprovided:

-   -   and pharmaceutically acceptable salts, solvates and prodrugs        thereof, wherein        -   X represents —NQ¹- or —CQ²=CQ³-;        -   Q¹, Q² and Q³ each independently represent H or C1 to C6            alkyl, preferably Q¹ is H, and Q² and Q³ each independently            represent H or methyl, more preferably Q¹, Q² and Q³ each            represent H;            R¹ and R² each independently represent H, halo, cyano, C1 to            C6 alkyl or C1 to C6 alkoxy, preferably R¹ and R² each            independently represent H or halo.

In another embodiment, Q¹ is H and X represents —NH— or —CQ²=CQ³-;

-   -   Q² and Q³ each independently represent H or C1 to C6 alkyl,        preferably Q² and Q³ each independently represent H or methyl,        more preferably Q² and Q³ each represent H;        R¹ and R² each independently represent H, halo, cyano, C1 to C6        alkyl or C1 to C6 alkoxy, preferably R¹ and R² each        independently represent H or halo.

In another embodiment, a composition comprising a compound of Formula I′and/or Formula I″ is provided. The composition may contain a racemiccompound. Alternatively, the composition may contain a mixture of acompounds of Formula I′ and Formula I″, which are produced separately.Such compounds may contain a 1:1 ratio of Formula I′ to Formula I″, asis present in the racemate, or the R-enantiomer may be present in anamount of greater than 50%. In another alternative, a composition maycontain more than 50% of the S-enantiomer. Optionally, the racemate, orone or both of the enantiomers, may be deuterated, e.g., at the chiralcarbon.

The invention further discloses a compound of Formula Ib

-   -   and pharmaceutically acceptable enantiomers, salts, solvates and        prodrugs thereof, wherein:        -   X represents —NQ¹- or —CQ²=CQ³-;        -   Q¹, Q² and Q³ each independently represent H or alkyl,            preferably Q′ is H, Q² and Q³ each independently represent H            or methyl, more preferably Q¹, Q² and Q³ represent H;        -   R^(1b) and R^(2b) each independently represent H, halo,            cyano, alkyl or alkoxy, preferably R^(1b) and R^(2b) each            independently represent H or halo;    -   under the condition that        -   when X represents —NQ¹-, then R^(1b) and R^(2b) are not both            H, and R^(1b) and R^(2b) are not both F; in one embodiment,            Q1 is H.        -   when X represents —CQ²=CQ³-, then R^(1b) and R^(2b) are not            both H.

In another embodiment, when Q1 is H, X represents —NH— or —CQ²=CQ³-

-   -   Q² and Q³ each independently represent H or alkyl, Q² and Q³        each independently represent H or methyl, more preferably Q² and        Q³ represent H;    -   R^(1b) and R^(2b) each independently represent H, halo, cyano,        alkyl or alkoxy, preferably R^(1b) and R^(2b) each independently        represent H or halo;    -   under the condition that    -   when X represents —NH—, then R^(1b) and R^(2b) are not both H,        and when X represents —NH—, R^(1b) and R^(2b) are not both F;        when X represents —CQ²=CQ³-, then R^(1b) and R^(2b) are not both        H.

According to one embodiment, the compound of Formula I′ is selected fromthe group consisting of:

-   (a) (−)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (b) (−)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (c) (−)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (d) (R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;    or-   (e) (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione,    or a pharmaceutically acceptable salt or solvate thereof. In another    embodiment, the compound of Formula II′ is selected from the group    consisting of:-   (a″) (S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (b″) (S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (c″) (S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (d″) (S)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;    or-   (e″) (S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione,    or a pharmaceutically acceptable salt or solvate thereof. In still    another embodiment, the compound of:-   3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione,-   3-(naphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; or-   3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione    or a pharmaceutically acceptable salt or solvate thereof, or a    deuterated form thereof.

The invention also discloses a process for manufacturing a compound ofFormula I′, I″ or Ib, comprising: reacting maleimide with a compound ofFormula (i) or (ib)

-   -   wherein X, R¹ and R² are as defined in Formula I′ or I″ and        R^(1b) and R^(2b) are as defined in Formula Ib, and optionally        separating enantiomers.

In another aspect, a compound having the structure of Formula II′:

or a pharmaceutically acceptable salt or solvate thereof is provided. Inone embodiment, the compound is a free base, i.e., is in neither saltnor solvate form. Also provided a pharmaceutical compositions containinga compound of Formula II′ alone, or optionally mixed or blended with acompound having the structure of Formula II″:

or a pharmaceutically acceptable salt thereof.

-   -   Other aspects and advantages of the invention will be apparent        from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of increasing amounts of compound 2of the invention on T-cell proliferation (as measured by Thymidineincorporation) in a SKOV-3-PBMC co-culture assay.

FIG. 2 is a graph showing the circulating Kynurenine concentration inhealthy mouse blood after treatment with compound 2 of the invention orwith a vehicle.

FIG. 3 is a graph of different studies showing the tumor growth of 4T1tumors in a mouse breast cancer model after treatment with compound 1 orwith a vehicle. FIG. 3 shows the tumor growth of 4T1 tumors aftertreatment with compound 1 at a dose of 100 mg/kg BID. The upper linerepresents vehicle and the lower line represents compound 1.

FIG. 4 is a graph showing the tumor growth of PanCO2 tumors in miceafter treatment with test compounds. The upper line represents vehicleand the lower line represents compound 1.

FIG. 5 is a graph showing the concentration of Kynurenine within a 4T1tumor in mice after treatment with compound 1 of the invention or with avehicle.

FIG. 6 is a graph showing the concentration of Kynurenine within a CT26tumor in mice after treatment with compound 1 of the invention or with avehicle.

FIG. 7 is a graph showing the tumor growth of CT26 tumors in Balb/c micein test Compound 1 at 200 mg/kg BID (open circle), 600 mg/kg BID (closedtriangle), as compared to vehicle (square).

DETAILED DESCRIPTION OF THE INVENTION Compounds Compounds of Formula I

and pharmaceutically acceptable enantiomers, salts, solvates andprodrugs thereof, wherein:

-   -   X represents —NQ¹- or —CQ²=CQ³-;    -   Q¹, Q² and Q³ each independently represent H or alkyl,        preferably Q¹, Q² and Q³ each independently represent H or        methyl, more preferably Q¹, Q² and Q³ represent H;    -   R¹ and R² each independently represent H, halo, cyano, alkyl or        alkoxy, preferably R¹ and R² each independently represent H or        halo.

In another embodiment, Q¹ is H, X represents —NH— or —CQ²=CQ³-;

-   -   Q² and Q³ each independently represent H or alkyl, preferably Q²        and Q³ each independently represent H or methyl, more preferably        Q² and Q³ represent H; R¹ and R² each independently represent H,        halo, cyano, alkyl or alkoxy, preferably R¹ and R² each        independently represent H or halo.

Also provided herein are compound of Formula I, and pharmaceuticallyacceptable enantiomers, salts, solvates and prodrugs thereof, which haveat least one deuterium atom substituted for a hydrogen atom. In oneembodiment, a compound of Formula I, or any of its subformulae providedherein, including Ia, Ib, I′, I, II, II′, II″, at the chiral center, asillustrated below in the structure of Formula Ia′

or a pharmaceutically acceptable enantiomer, salt, solvate or prodrugthereof. Formulae I, Ia and Ib are drawn without reference tostereochemistry, and thus each encompasses a racemic compound, andseparate stereoisomers, i.e., the R- and/or S-stereoisomer. In oneembodiment, these stereoisomers may have the structure of Formula I′(R-stereoisomer) and Formula II′ (S-enantiomer).

Illustrative compounds of Formula I are shown in the table and examplesherein and include:

-   3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+)-(S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+−)-(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+)-(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (S)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile;-   3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;-   3-(naphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; and-   3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione.

Optionally, these compounds of Formula I may be deuterated, e.g., at thechiral center. An illustrated deuterated compound(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione is provided inthe examples below. Other deuterated compounds may include, e.g.,

-   (−)-(R)-(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+)-(S)-(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-(3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+−)-(S)-(3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-(3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+)-(S)-(3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-(3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (S)-(3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (S)-(3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile;-   (3-²H)-3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;-   (3-²H)-3-(naphthalen-1-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   (3-²H)-3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; and-   (3-²H)-3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione,

In one embodiment, preferred compounds of Formula I are those of FormulaI′ or I″

and pharmaceutically acceptable, salts, solvates and prodrugs thereof,wherein X, R¹ and R² areas defined in Formula I.

As described herein, a racemic compound of Formula I may contain about50% of a compound of Formula I′ and about 50% of Formula I″ based on amolar ratio (about 48 to about 52 mol %, or about a 1:1 ratio)) of oneof the isomers. In another embodiment, a composition, medicament, ormethod of treatment may involve combining separately produced compoundsof Formula I′ and Formula I″ in an approximately equal molar ratio(about 48 to 52%). In another embodiment, a medicament or pharmaceuticalcomposition may contain a mixture of separate compounds of Formula I′and Formula I″ in different ratios. In one embodiment, thepharmaceutical composition contains an excess (greater than 50%) of theR-enantiomer (Formula I′). Suitable molar ratios of IRIS may be fromabout 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In another embodiment,a pharmaceutical composition may contain an excess of the S-enantiomer(Formula I″), with the ratios provided for R/S reversed. Other suitableamounts of R/S may be selected. For example, the R-enantiomer may bepresent in amounts of at least about 55% to 100%, or at least 65%, atleast 75%, at least 80%, at least 85%, at least 90%, about 95%, about98%, or 100%. In other embodiments, the S-enantiomer may be present in ahigher percentage, e.g., in amounts of at least about 55% to 100%, or atleast 65%, at least 75%, at least 80%, at least 85%, at least 90%, about95%, about 98%, or 100%. Ratios between all these exemplary embodimentsas well as greater than and less than them while still within theinvention, all are included. (The term “ratio” as used herein (above andbelow) refers always to the molar ratio). Compositions may contain amixture of the racemate and a separate compound of Formula I′ and/orFormula I″, in free base and/or in salt form.

Optionally, the racemate, or one or both of the enantiomers, may bedeuterated. Such deuterated compounds may be in salt form. For example,the deuterated stereoisomers may be characterized by the structure:

wherein X (or X^(a)), R¹, and R² are as defined above in Formula I andIa. Without wishing to be bound by theory, it has been described in theliterature generally that one enantiomer (isomer or stereoisomer) canconvert in plasma to the racemate and/or to the other enantiomer. It isbelieved that deuteration at the chiral center of these compounds slowsthe conversion of the individual stereoisomers to the racemate and/orthe other stereoisomer in plasma.

In one embodiment, preferred compounds of Formula I are those of FormulaIa

and pharmaceutically acceptable enantiomers, salts, solvates andprodrugs thereof, wherein:

-   -   X^(a) represents —NH— or —CQ²=CQ³-;    -   Q² and Q³ each independently represent H or alkyl, preferably Q²        and Q³ each independently represent H or methyl, more preferably        Q² and Q³ represent H;    -   R¹ and R² each independently represent H, halo, cyano, alkyl or        alkoxy, preferably R¹ and R² each independently represent H or        halo.

In one embodiment, preferred compounds of Formula I are those of FormulaIb

and pharmaceutically acceptable enantiomers, salts, solvates andprodrugs thereof, wherein:

-   -   X represents —NQ¹- or —CQ²=CQ³-;    -   Q¹, Q² and Q³ each independently represent H or alkyl;        optionally, the alkyl is C1 to C6 alkyl, preferably Q¹, Q² and        Q³ each independently represent H or methyl, more preferably Q¹,        Q² and Q³ represent H;    -   R^(1b) and R^(2b) each independently represent H, halo, cyano,        alkyl or alkoxy; optionally, the alkyl is C1 to C6 alkyl and the        alkoxy is C1 to C6 alkoxy, preferably R^(1b) and R^(2b) each        independently represent H or halo;        under the condition that    -   when X represents —NQ¹-, then R^(1b) and R^(2b) are not both H,        and R^(1b) and R^(2b) are not both F;    -   when X represents —CQ²=CQ³-, then R^(1b) and R^(2b) are not both        H.

In another embodiment, Q¹ is H and X represents —NH¹- or —CQ²=CQ³-;

-   -   Q² and Q³ each independently represent H or alkyl; optionally,        the alkyl is C1 to C6 alkyl, preferably Q² and Q³ each        independently represent H or methyl, more preferably Q² and Q³        represent H;    -   R^(1b) and R^(2b) each independently represent H, halo, cyano,        alkyl or alkoxy; optionally, the alkyl is C1 to C6 alkyl and the        alkoxy is C1 to C6 alkoxy, preferably R^(1b) and R^(2b) each        independently represent H or halo;        under the condition that    -   when X represents —NH—, then R^(1b) and R^(2b) are not both H,        and R^(1b) and R^(2b) are not both F;    -   when X represents —CQ²=CQ³-, then R^(1b) and R^(2b) are not both        H.

Particularly preferred compounds of Formula I of the invention are thoselisted in Table 1 hereafter.

TABLE 1 Cpd n° Structure Chemical name  1

3-(5-fluoro-1H-indol-3- yl)pyrrolidine-2,5-dione  1a

(3-²H)-3-(5-fluoro-1H- indol-3-yl)pyrrolidine- 2,5-dione  2

(−)-(R)-3-(5-fluoro-1H- indol-3-yl)pyrrolidine- 2,5-dione  3

3-(1H-indol-3-yl) pyrrolidine-2,5-dione  4

(−)-(R)-3-(1H-indol-3- yl)pyrrolidine-2,5-dione  5

3-(5-chloro-1H-indol-3- yl)pyrrolidine-2,5-dione  6

(−)-(R)-3-(5-chloro-1H- indol-3-yl)pyrrolidine- 2,5-dione  7

3-(6-chloro-5-fluoro-1H- indol-3-yl)pyrrolidine- 2,5-dione  8

(R)-3-(6-chloro-5- fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione  9

3-(6-bromo-5-fluoro- 1H-indol-3-yl) pyrrolidine-2,5-dione 10

(R)-3-(6-bromo-5- fluoro-1H-indol-3-yl) pyrrolidine-2,5-dione 11

3-(5-bromo-1H-indol-3- yl)pyrrolidine-2,5-dione 12

3-(5-methyl-1H-indol-3- yl)pyrrolidine-2,5-dione 13

3-(5-methoxy-1H-indol- 3-yl)pyrrolidine-2,5- dione 14

3-(2,5-dioxopyrrolidin- 3-yl)-1H-indole-5- carbonitrile 15

3-(5,6-difluoro-1H- indol-3-yl)pyrrolidine- 2,5-dione 16

3-(5-fluoro-6-methyl- 1H-indol-3-yl) pyrrolidine-2,5-dione 17

3-(6-fluoro-1H-indol-3- yl)pyrrolidine-2,5-dione 18

3-(6-chloro-1H-indol-3- yl)pyrrolidine-2,5-dione 19

3-(6-bromo-1H-indol-3- yl)pyrrolidine-2,5-dione 20

3-(6-methyl-1H-indol-3- yl)pyrrolidine-2,5-dione 21

3-(6-methoxy-1H-indol- 3-yl)pyrrolidine-2,5- dione 22

3-(2,5-dioxopyrrolidin- 3-yl)-1H-indole-6- carbonitrile 23

3-(naphthalen-1-yl) pyrrolidine-2,5-dione 24

3-(6-fluoronaphthanlen- 1-yl)pyrrolidine-2,5- dione 25

3-(7-fluoronaphthanlen- 1-yl)pyrrolidine-2,5- dione 26

3-(6-chloronaphthalen- 1-yl)pyrrolidine-2,5- dione 27

3-(7-chloronaphthalen- 1-yl)pyrrolidine-2,5- dioneor pharmaceutically acceptable enantiomers, salts, solvates and prodrugsthereof.

In Table 1, the term “Cpd” means compound.

The compounds of Table 1 were named using ChemBioDraw® Ultra version12.0 (PerkinElmer).

According to a preferred embodiment, particularly preferred compounds ofFormula I of the invention are compounds of Table 1 n° I, la, 2, 4, 6,7, 8, 9, 10, 14, 16, 22, 24, 25, 26, 27.

The compounds of Formula I and subformulae thereof contain an asymmetriccenter and thus exist as different stereoisomeric forms. Accordingly,the present invention includes all possible stereoisomers and includesnot only racemic compounds but the individual enantiomers and theirnon-racemic mixtures as well. When a compound is desired as a singleenantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as each are known in the art. Resolutionof the final product, an intermediate, or a starting material may beperformed by any suitable method known in the art.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts of the compounds ofFormula I include base salts, which form non-toxic salts including,e.g., aluminum, calcium, choline, magnesium, potassium, sodium, zinc,and tetramethylammonium hydroxide. Although less desired, other basesmay be selected, including, e.g., ammonia, ethylenediamine,N-methyl-glutamine, lysine, arginine, ornithine,N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethyl-amine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, benzathine, diethylamine, diolamine,glycine, lysine, meglumine, olamine, tromethamine,2-(diethylamino)ethanol, ethanolamine, morpholine, and4-(2-hydroxyethyl)morpholine. Hemisalts of bases may also be formed, forexample, hemicalcium salts.

Pharmaceutically acceptable salts of compounds of Formula I may beprepared by one or more of these methods:

-   -   (i) by reacting the compound of Formula I and its subformulae        with the desired base;    -   (ii) by removing an acid- or base-labile protecting group from a        suitable precursor of the compound of Formula I (or its        subformulae) or by ring-opening a suitable cyclic precursor, for        example, a lactone or lactam, using the desired acid; or    -   (iii) by converting one salt of the compound of Formula I (or        its subformulae) to another by reaction with an appropriate acid        or by means of a suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in thesalt may vary from completely ionized to almost non-ionized.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” is intended to include all acceptable salts such as canbe used as a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-drugformulations. Depending on the particular functionality of the compoundof the present invention, pharmaceutically acceptable salts of thecompounds of this invention include those formed from cations such assodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and frombases such as, and tetramethylammonium hydroxide.

These salts may be prepared by standard procedures, e.g. by reacting afree acid with a suitable organic or inorganic base. Where a basic groupis present, such as amino, an acidic salt, i.e. hydrochloride,hydrobromide, acetate, palmoate, and the like, can be used as the dosageform.

Also, in the case of an alcohol group being present, pharmaceuticallyacceptable esters can be employed, e.g. acetate, maleate,pivaloyloxymethyl, and the like, and those esters known in the art formodifying solubility or hydrolysis characteristics for use as sustainedrelease or prodrug formulations.

All references to compounds of Formula I include references toenantiomers, salts, solvates, polymorphs, multi-component complexes andliquid crystals thereof.

The compounds of the invention include compounds of Formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) and isotopically-labeled compounds of Formula I.

In addition, although generally, with respect to the salts of thecompounds of the invention, pharmaceutically acceptable salts arepreferred, it should be noted that the invention in its broadest sensealso included non-pharmaceutically acceptable salts, which may forexample be used in the isolation and/or purification of the compounds ofthe invention. For example, salts formed with optically active acids orbases may be used to form diastereoisomeric salts that can facilitatethe separation of optically active isomers of the compounds of Formula Iabove.

As used herein, the term “free base” refers to the non-salt form of acompound of Formula I.

Unless otherwise specified, reference to Formula I herein includes itssubformulae, such as Formula Ia, Ib, la′, I′, I″, II, II′, and II″.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formula I.

Process for Manufacturing

The compounds of Formula I can be prepared by different ways withreactions known to a person skilled in the art.

The invention further relates to a first process for manufacturing ofcompounds of Formula I

-   -   and pharmaceutically acceptable enantiomers, salts, solvates and        prodrugs thereof, wherein X, R¹ and R² are as defined in Formula        I;    -   comprising    -   reacting a compound of Formula (i)

-   -   wherein X, R¹ and R² areas defined in Formula I    -   with maleimide to provide compound of Formula I;    -   and optionally separating enantiomers of Formula I′ and I″.

According to one embodiment, the process may be performed in thepresence of a suitable solvent such as but not limited to acetic acid,acetonitrile, DMSO, dichloroethane, DMF, water or mixtures thereof,preferably in acetic acid or acetonitrile. According to one embodiment,the process may be performed in the presence or absence of a suitablecatalyst, such as but not limited to protic acids such as but notlimited to acetic acid, hydrochloric acid or sulfuric acid; or Lewisacids such as but not limited to zinc chloride, zinc acetate, zinctriflate, aluminum chloride, cobalt chloride, cobalt acetate or ironchloride

According to one embodiment, the process may be performed at atemperature ranging from 20° C. to about 200° C., preferably at atemperature ranging from 60° C. to 200° C., or about 150° C. to about200° C., with or without microwave irradiation, for a period rangingfrom 10 minutes to a few hours, e.g. 10 minutes to 48 h.

According to one embodiment, the optional separation of the enantiomersof Formula I′ and I″ starting from the corresponding compound of FormulaI can be achieved by chiral HPLC, such as but not limited to using aChiralpak® AS-H, Chiralcel® OJ-H or Chiralpak® IC column, using aseluents mixtures of appropriate solvents such as but not limited tosupercritical CO₂, ethanol, methanol, hexane.

According to one embodiment, the optional separation of the enantiomersof Formula I′ and I″ starting from the corresponding compound of FormulaI can be achieved by resolution using optically pure acids, such as butnot limited to camphosulfonic acid or tartaric acid, or with opticallypure bases, such as but not limited to brucine, depending on the natureof the compound of Formula I.

The invention further relates to a second process of manufacturing ofcompounds of Formula I

-   -   and pharmaceutically acceptable enantiomers, salts, solvates and        prodrugs thereof, wherein X, R¹ and R² are as defined in Formula        I;    -   comprising reacting a compound of Formula (ii)

-   -   wherein X, R¹ and R² are as defined in Formula I; and Z¹ and Z²        represent H or alkyl groups, with the possibility for Z¹ and Z²        to form a ring;    -   with maleimide to provide compound of Formula I;    -   and optionally separating enantiomers of Formula I′ and I″.

According to one embodiment, the process may be performed with orwithout a catalyst such as but not limited to [RhOH(cod)]₂.

According to one embodiment, the process may be performed in thepresence of bases such as but not limited to trimethylamine (TEA),diethylisopropylamine (DIEA), sodium hydroxide (NaOH), potassiumhydroxide (KOH), tripotassium phosphate (K₃PO₄), dipotassium carbonate(K₂CO₃), disodium carbonate (Na₂CO₃), preferably TEA or DIEA.

According to one embodiment, the process may be performed in thepresence of a suitable solvent such as but not limited to dioxane,tetrahydrofuran (THF), dimethylformamide (DMF), water or mixturesthereof, preferably in dioxane or THF.

According to one embodiment, the process may be performed at atemperature ranging from 20° C. to about 150° C., with or withoutmicrowave irradiation, for a period ranging from 10 minutes to a fewhours, e.g. 10 minutes to 24 h.

According to one embodiment, the optional separation of the enantiomersof Formula I′ and I″ starting from the corresponding compound of FormulaI can be achieved by chiral HPLC, such as but not limited to using aChiralpak® AS-H, Chiralcel® OJ-H or Chiralpak® IC column, using aseluents mixtures of appropriate solvents such as but not limited tosupercritical CO₂, ethanol, methanol, hexane.

According to one embodiment, the optional separation of the enantiomersof Formula I′ and I″ starting from the corresponding compound of FormulaI can be achieved by resolution using optically pure acids, such as butnot limited to camphosulfonic acid or tartaric acid, or with opticallypure bases, such as but not limited to brucine, depending on the natureof the compound of Formula I.

The invention further relates to a third process of manufacturing ofcompounds of Formula I

-   -   and pharmaceutically acceptable enantiomers, salts, solvates and        prodrugs thereof, wherein X, R¹ and R² areas defined in Formula        I;    -   comprising        -   (a) reacting a compound of Formula (iii)

-   -   wherein X, R¹ and R² are as defined in Formula I;        -   so as to obtain a compound of Formula (iv)

-   -   wherein X, R¹ and R² are as defined in Formula I;        -   (b) reacting compound of Formula (iv) with maleic anhydride            so as to obtain compound of Formula (v)

-   -   wherein X, R¹ and R² are as defined in Formula I;        -   and        -   (c) reacting compound of Formula (iv) with urea so as to            obtain compound of Formula I        -   (d) optionally separating enantiomers of Formula I′ and I″.

According to one embodiment, step (a) may be performed in the presenceof a nitrite, such as but not limited to NaNO₂, KNO₂, tert-butyl nitriteor isoamyl nitrite.

According to one embodiment, step (a) may be performed in the presenceof a suitable acid, such as but not limited to HBF₄.

According to one embodiment, step (a) may be performed in the presenceof a suitable solvent such as but not limited to water.

According to one embodiment, step (a) may be performed at a temperatureranging from −20° C. to about 20° C., preferably at 0° C.

According to one embodiment, step (a) may be performed for a periodranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, step (b) may be performed in the presenceof a suitable catalyst, such as but not limited to TiCl₃.

According to one embodiment, step (b) may be performed in the presenceof a suitable base, such as but not limited to NaOH or KOH.

According to one embodiment, step (b) may be performed in the presenceof a suitable solvent such as but not limited to acetone, methyl ethylketone.

According to one embodiment, step (b) may be performed at a temperatureranging from −20° C. to about 20° C., preferably at 0° C.

According to one embodiment, step (b) may be performed for a periodranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, step (c) may be performed in the absence orpresence of a suitable solvent, at a temperature ranging from 100° C. toabout 200° C., preferably at 180° C.

According to one embodiment, step (c) may be performed for a periodranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, the optional separation of the enantiomersof Formula I′ and I″ starting from the corresponding compound of FormulaI can be achieved by chiral HPLC, such as but not limited to using aChiralpak® AS-H, Chiralcel® OJ-H or Chiralpak® IC column, using aseluents mixtures of appropriate solvents such as but not limited tosupercritical CO₂, ethanol, methanol, hexane.

According to one embodiment, the optional separation of the enantiomersof Formula I′ and I″ starting from the corresponding compound of FormulaI can be achieved by resolution using optically pure acids, such as butnot limited to camphosulfonic acid or tartaric acid, or with opticallypure bases, such as but not limited to brucine, depending on the natureof the compound of Formula I.

In general, the synthesis pathways for any individual compound ofFormula I will depend on the specific substituents of each molecule andupon the ready availability of intermediates necessary; again suchfactors being appreciated by those of ordinary skill in the art.

According to a further general process, compounds of Formula I can beconverted to alternative compounds of Formula I, employing suitableinterconversion techniques well known by a person skilled in the art.

Compounds of the Formula I and related formulae can furthermore beobtained by liberating compounds of the Formula I from one of theirfunctional derivatives by treatment with a solvolysing orhydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to the Formula I and related formulae, but containcorresponding protected amino and/or hydroxyl groups instead of one ormore free amino and/or hydroxyl groups, preferably those which carry anamino-protecting group instead of an H atom bonded to an N atom, inparticular those which carry an R*—N group, in which R* denotes anamino-protecting group, instead of an HN group, and/or those which carrya hydroxyl-protecting group instead of the H atom of a hydroxyl group,for example those which conform to the Formula I, but carry a —COOR**group, in which R** denotes a hydroxyl-protecting group, instead of a—COOH group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl)and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl,such as Mtr. Preferred amino-protecting groups are BOC and Mtr,furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easy to remove after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred.

The compounds of the Formula I and related formulae are liberated fromtheir functional derivatives—depending on the protecting group used—forexample strong inorganic acids, such as hydrochloric acid, perchloricacid or sulfuric acid, strong organic carboxylic acids, such astrichloroacetic acid, TFA or sulfonic acids, such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible, but is not always necessary. Suitable inert solvents arepreferably organic, for example carboxylic acids, such as acetic acid,ethers, such as THF or dioxane, amides, such as DMF, halogenatedhydrocarbons, such as dichloromethane, furthermore also alcohols, suchas methanol, ethanol or isopropanol, and water. Mixtures of theabove-mentioned solvents are furthermore suitable. Trifluoracetic acid(TFA) is preferably used in excess without addition of a furthersolvent, and perchloric acid is preferably used in the form of a mixtureof acetic acid and 70% perchloric acid in the ratio 9:1. The reactiontemperatures for the cleavage are advantageously between about 0 andabout 50° C., preferably between 15 and 30° C. (room temperature).

The BOC, OtBu and Mtr groups can, for example, preferably be cleaved offusing TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30° C., and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30° C.

Protecting groups which can be removed hydrogenolytically (for exampleCBZ, benzyl or the liberation of the amidino group from the oxadiazolederivative thereof) can be cleaved off, for example, by treatment withhydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° C. and pressures between about 1and 200 bar, preferably at 20-30° C. and 1-10 bar. Hydrogenolysis of theCBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol orusing ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at20-30° C.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid oracetic acid; nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents.

Esters can be hydrolysed, for example, using HCl, H₂SO₄, or using LiOH,NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, attemperatures between 0 and 100° C.

Free amino groups can furthermore be acylated in a conventional mannerusing an acyl chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60° C. and +30° C.

For all the protection and deprotection methods, see Philip J.Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, NewYork, 1994 and, Theodora W. Greene and Peter G. M. Wuts in “ProtectiveGroups in Organic Synthesis”, Wiley Interscience, 3rd Edition 1999.

Reaction schemes as described in the example section are illustrativeonly and should not be construed as limiting the invention in any way.

Uses

The invention is further directed to a medicament comprising at leastone compound of the invention, or a pharmaceutically acceptableenantiomer, salt, solvate and prodrug thereof, or a deuterated formthereof, as active ingredient.

In the present invention, the expression “compound of the invention”encompasses compounds of Formula I and its subformulae, or apharmaceutically acceptable enantiomer, salt, solvate and prodrugthereof, or a deuterated form thereof. Examples are identified in Table1 and in the examples. Illustrative compounds include:

-   3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+)-(S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+−)-(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (−)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (+)-(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (S)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   (S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile;-   3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;-   3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;-   3-(naphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;-   3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; and-   3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione.

Optionally, these compounds of Formula I may be deuterated, e.g., at thechiral center. An illustrated deuterated compound is(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione.

-   -   In one embodiment, the compound has the structure of Formula II:

or a pharmaceutically acceptable salt thereof. The compound may be aracemate, wherein each stereoisomer is present an amount of about 50 mol% (48% to 52%). Alternatively or additionally, a separate enantiomer ofthe compound is used in a pharmaceutical composition. In one embodiment,the enantiomer is characterized by structure of Formula II′:

which is present in free base (not salt) form. Optionally, the compoundis present as a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment, the (S)-enantiomer is additionally or alternativelypresent in the composition. This enantiomer is characterized by thestructure of Formula II″:

which is in free base form, or optionally may be salt form.Pharmaceutical compositions may contain mixtures of the compounds ofFormula II′ and Formula II″. A variety of ratios of the two compoundsmay be selected. For example, the ratio may be about 1:1, or thecompound of Formula II′ may be present in greater than 50%, greater than95%, greater than 90%, or about 95% to 100%.

Similarly, in other compositions, the compound of Formula II″ may bepresent in greater than 50%. The discussion of suitable ratios and molarpercentages of enantiomers relating to the compounds of Formula I andits subformulae earlier in the specification, is hereby incorporated byreference.

The invention also provides pharmaceutical compositions comprising acompound of the invention or a pharmaceutically acceptable enantiomer,salt, solvate and prodrug thereof and at least one pharmaceuticallyacceptable carrier, diluent, excipient and/or adjuvant. The carrier(s)are “acceptable” in the sense of being compatible with the otheringredients of the formulation and, in the case of a pharmaceuticallyacceptable carrier, not deleterious to the recipient thereof in anamount used in the medicament.

According to one embodiment, the invention also covers pharmaceuticalcompositions which contain, in addition to a compound of the presentinvention or a pharmaceutically acceptable enantiomer, salt, solvate andprodrug thereof as active ingredient, additional therapeutic agentsand/or active ingredients.

By means of non-limiting examples, the compounds of the invention may beformulated as a pharmaceutical preparation in a form suitable for oraladministration, for parenteral administration (such as by intravenous,intramuscular or subcutaneous injection or intravenous infusion), fortopical administration (including ocular), for administration byinhalation, by a skin patch, by an implant, by a suppository, etc. Suchsuitable administration forms—which may be solid, semi-solid or liquid,depending on the manner of administration—as well as methods andcarriers, diluents and excipients for use in the preparation thereof,will be clear to the skilled person; reference is made to the latestedition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes,lotions, soft and hard gelatin capsules, suppositories, drops, sterileinjectable solutions and sterile packaged powders (which are usuallyreconstituted prior to use) for administration as a bolus and/or forcontinuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other substances that are commonly used inpharmaceutical formulations, such as lubricating agents, wetting agents,emulsifying and suspending agents, dispersing agents, desintegrants,bulking agents, fillers, preserving agents, sweetening agents, flavoringagents, flow regulators, release agents, etc. The compositions may alsobe formulated so as to provide rapid, sustained or delayed release ofthe active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use.

Depending on the condition to be prevented or treated and the route ofadministration, the active compound of the invention may be administeredas a single daily dose, divided over one or more daily doses, oressentially continuously, e.g. using a drip infusion.

The invention also relates to the use of compounds of the invention, orpharmaceutically acceptable enantiomers, salts, solvates and prodrugsthereof, in the treatment and/or prevention of cancer and endometriosis.In one embodiment, the invention relates to the use of compounds of theinvention, or pharmaceutically acceptable enantiomers, salts, solvatesand prodrugs thereof, in the treatment and/or prevention of cancer. Inanother embodiment, the invention relates to the use of compounds of theinvention, or pharmaceutically acceptable enantiomers, salts, solvatesand prodrugs thereof, in the treatment and/or prevention ofendometriosis.

In one embodiment, compounds of the invention or pharmaceuticallyacceptable enantiomers, salts, solvates or prodrugs thereof are for usein the treatment and/or prevention of cancer and endometriosis.According to one embodiment, compounds of the invention, orpharmaceutically acceptable enantiomers, salts, solvates and prodrugsthereof, are for use in the treatment and/or prevention of cancer.According to another embodiment, compounds of the invention, orpharmaceutically acceptable enantiomers, salts, solvates and prodrugsthereof, are for use in the treatment and/or prevention ofendometriosis.

The invention further relates to a method for treatment or prevention ofcancer and endometriosis, which comprises administering to a subject inneed thereof a therapeutically effective amount of the compoundaccording to the invention or a pharmaceutically acceptable enantiomers,salts, solvates or prodrugs thereof. In one embodiment, the inventionrelates to a method for treatment or prevention of cancer, whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of the compound according to the invention or apharmaceutically acceptable enantiomers, salts, solvates or prodrugsthereof. In another embodiment, the invention relates to a method fortreatment or prevention of endometriosis, which comprises administeringto a subject in need thereof a therapeutically effective amount of thecompound according to the invention or a pharmaceutically acceptableenantiomers, salts, solvates or prodrugs thereof.

In one embodiment, compounds of the invention or pharmaceuticallyacceptable enantiomers, salts, solvates or prodrugs thereof are for usein increasing immune recognition and destruction of the cancer cells.

The compounds of the invention are therefore useful as medicaments, inparticular in the prevention and/or treatment of cancer.

The invention further provides the use of a compound according to theinvention or a pharmaceutically acceptable enantiomer, salt, solvate andprodrug thereof for the manufacture of a medicament for treating and/orpreventing cancer.

Various cancers are known in the art. The cancer may be metastatic ornon-metastatic. The cancer may be may be familial or sporadic. In someembodiments, the cancer is selected from the group consisting of:leukemia and multiple myeloma. In one embodiment, the cancer isleukemia. In one embodiment, the cancer is multiple myeloma.

Additional cancers that can be treated using the methods of theinvention include, for example, benign and malignant solid tumors andbenign and malignant non-solid tumors. In one embodiment, the cancer isbenign solid tumors. In one embodiment, the cancer is malignant solidtumors. In one embodiment, the cancer is benign non-solid tumors. In oneembodiment, the cancer is malignant non-solid tumors.

Examples of solid tumors include, but are not limited to: biliary tractcancer, brain cancer (including glioblastomas and medulloblastomas),breast cancer, cervical cancer, choriocarcinoma, colon cancer,endometrial cancer, esophageal cancer, gastric cancer, intraepithelialneoplasms (including Bowen's disease and Paget's disease), liver cancer,lung cancer, neuroblastomas, oral cancer (including squamous cellcarcinoma), ovarian cancer (including those arising from epithelialcells, stromal cells, germ cells and mesenchymal cells), pancreaticcancer, prostate cancer, rectal cancer, renal cancer (includingadenocarcinoma and Wilms tumour), sarcomas (including leiomyosarcoma,rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skincancer (including melanoma, Kaposi's sarcoma, basocellular cancer andsquamous cell cancer), testicular cancer including germinal tumors(seminomas, and non-seminomas such as teratomas and choriocarcinomas),stromal tumors, germ cell tumors, and thyroid cancer (including thyroidadenocarcinoma and medullary carcinoma).

In one embodiment, the cancer is biliary tract cancer. In oneembodiment, the cancer is brain cancer, including glioblastomas andmedulloblastomas. In one embodiment, the cancer is breast cancer. In oneembodiment, the cancer is cervical cancer. In one embodiment, the canceris choriocarcinoma. In one embodiment, the cancer is colon cancer. Inone embodiment, the cancer is endometrial cancer. In one embodiment, thecancer is esophageal cancer. In one embodiment, the cancer is gastriccancer. In one embodiment, the cancer is intraepithelial neoplasms,including Bowen's disease and Paget's disease. In one embodiment, thecancer is liver cancer. In one embodiment, the cancer is lung cancer. Inone embodiment, the cancer is neuroblastomas. In one embodiment, thecancer is oral cancer, including squamous cell carcinoma. In oneembodiment, the cancer is ovarian cancer, including those arising fromepithelial cells, stromal cells, germ cells and mesenchymal cells. Inone embodiment, the cancer is pancreatic cancer. In one embodiment, thecancer is prostate cancer. In one embodiment, the cancer is rectalcancer. In one embodiment, the cancer is renal cancer, includingadenocarcinoma and Wilms tumour. In one embodiment, the cancer issarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma,fibrosarcoma and osteosarcoma. In one embodiment, the cancer is skincancer, including melanoma, Kaposi's sarcoma, basocellular cancer andsquamous cell cancer. In one embodiment, the cancer is testicular cancerincluding germinal tumors (seminomas, and non-seminomas such asteratomas and choriocarcinomas). In one embodiment, the cancer isstromal tumors. In one embodiment, the cancer is germ cell tumors. Inone embodiment, the cancer is thyroid cancer, including thyroidadenocarcinoma and medullary carcinoma.

Examples of non-solid tumors include but are not limited tohematological neoplasms. As used herein, a hematologic neoplasm is aterm of art which includes lymphoid disorders, myeloid disorders, andAIDS associated leukemias.

Lymphoid disorders include but are not limited to acute lymphocyticleukemia and chronic lymphoproliferative disorders (e.g., lymphomas,myelomas, and chronic lymphoid leukemias). Lymphomas include, forexample, Hodgkin's disease, non-Hodgkin's lymphoma lymphomas, andlymphocytic lymphomas). Chronic lymphoid leukemias include, for example,T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.

In one embodiment, the lymphoid disorder is acute lymphocytic leukemia.In one embodiment, the lymphoid disorder is chronic lymphoproliferativedisorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias).In one embodiment, the lymphoma is Hodgkin's disease. In one embodiment,the lymphoma is non-Hodgkin's lymphoma. In one embodiment, the lymphomais lymphocytic lymphoma. In one embodiment, the chronic lymphoidleukemia is T cell chronic lymphoid leukemia. In one embodiment, thechronic lymphoid leukemia is B cell chronic lymphoid leukemia.

The invention also provides for a method for delaying in a subject theonset of cancer comprising the administration of a pharmaceuticallyeffective amount of a compound according to the invention orpharmaceutically acceptable enantiomer, salt, solvate and prodrugthereof to a subject in need thereof.

The invention is further directed to the use of compounds of theinvention, or pharmaceutically acceptable enantiomers, salts, solvatesand prodrugs thereof as IDO1 inhibitors.

Accordingly, in a particularly preferred embodiment, the inventionrelates to the use of compounds of Formula I and subformulae inparticular those of Table 1 above, or pharmaceutically acceptableenantiomers, salts, solvates and prodrugs thereof, as IDO1 inhibitors.

Accordingly, in another aspect, the invention relates to the use ofthese compounds or enantiomers, salts, solvates and prodrugs thereof forthe synthesis of IDO1 inhibitors.

According to a further feature of the present invention there isprovided a method for modulating IDO1 activity, in a subject in need ofsuch treatment, which comprises administering to said subject aneffective amount of compound of the present invention, or apharmaceutically acceptable enantiomer, salt, solvate and prodrugthereof.

According to a further feature of the present invention there isprovided the use of a compound of the invention or a pharmaceuticallyacceptable enantiomer, salt, solvate and prodrug thereof for themanufacture of a medicament for modulating IDO1 activity in a subject inneed of such treatment, which comprises administering to said subject aneffective amount of compound of the present invention, or apharmaceutically acceptable enantiomer, salt, solvate and prodrugthereof.

DEFINITIONS

In the present invention, the following terms have the followingmeanings:

Where groups may be substituted, such groups may be substituted with oneor more substituents, and preferably with one, two or threesubstituents. Substituents may be selected from but not limited to, forexample, the group comprising halogen, hydroxyl, oxo, nitro, amido,carboxy, amino, cyano, haloalkoxy, and haloalkyl.

The term “halogen” or “halo” means fluoro (F), chloro (Cl), bromo (Br),or iodo (I). Preferred halo groups are fluoro and chloro.

The term “alkyl” by itself or as part of another substituent refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numbergreater than or equal to 1. Generally, alkyl groups of this inventioncomprise from 1 to 6 carbon atoms (C1, C2, C3, C4, C5, or C6 carbons,inclusive), preferably from 1 to 4 carbon atoms, more preferably from 1to 3 carbon atoms. Alkyl groups may be linear or branched and may besubstituted as indicated herein. Suitable alkyl groups include methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyland its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers(e.g. n-hexyl, iso-hexyl). Optionally, an alkyl may be substituted with1, 2 or 3 substituents. Such a substituent may be a hydroxy, amino-,halogen, or C1-C3 alkyl group. In one embodiment, a halogen substituentis a F or Br. In another embodiment, an alkyl substituent is a methylgroup. The term “alkoxy” refers to any group O-alkyl.

The term “amino” refers to a —NH₂ group or any group derived thereof bysubstitution of one nor two hydrogen atom by an organic aliphatic oraromatic group. Preferably, groups derived from —NH₂ are “alkylamino”groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino.According to a specific embodiment, the term “amino” refers to NH₂, NHMeor NMe₂.

The term “amino-protecting group” refers to a protecting group for anamine function. According to a preferred embodiment, theamino-protecting group is selected in the groups comprising:arylsulphonyl, tert-butoxy carbonyl, methoxymethyl, para-methoxy benzylor benzyl.

The term “solvate” is used herein to describe a compound in thisinvention that contains stoichiometric or sub-stoichiometric amounts ofone or more pharmaceutically acceptable solvent molecule such asethanol. The term “hydrate” refers to when the said solvent is water.

The compounds of the invention include compounds of Formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and prodrugs thereof and isotopically-labeledcompounds of Formula I.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formula I.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of compounds of Formula I, such as for example amides, whosein vivo biotransformation product generates the biologically activedrug. Prodrugs are generally characterized by increased bio-availabilityand are readily metabolized into biologically active compounds in vivo.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The term “subject” refers to a mammal, preferably a human. In oneembodiment, a subject may be a “patient”, i.e. a warm-blooded animal,more preferably a human, who/which is awaiting the receipt of, or isreceiving medical care or was/is/will be the object of a medicalprocedure, or is monitored for the development of a disease.

The term “human” refers to a person of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The terms “treat”, “treating” and “treatment”, as used herein, are meantto include alleviating, attenuating or abrogating a condition or diseaseand/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention”, as used herein,refer to a method of delaying or precluding the onset of a condition ordisease and/or its attendant symptoms, barring a subject from acquiringa condition or disease, or reducing a subject's risk of acquiring acondition or disease.

The term “therapeutically effective amount” (or more simply an“effective amount”) as used herein means the amount of active agent oractive ingredient that is sufficient to achieve the desired therapeuticor prophylactic effect in the subject to which/whom it is administered.

The term “administration”, or a variant thereof (e.g. “administering”),means providing the active agent or active ingredient, alone or as partof a pharmaceutically acceptable composition, to the subject inwhom/which the condition, symptom, or disease is to be treated orprevented.

By “pharmaceutically acceptable” is meant that the ingredients of apharmaceutical composition are compatible with each other and notdeleterious to the subject to which it is administered.

The term “inhibitor” refers to a natural or synthetic compound that hasa biological effect to inhibit or significantly reduce or down-regulatethe expression of a gene and/or a protein or that has a biologicaleffect to inhibit or significantly reduce the biological activity of aprotein. Consequently, an “IDO1 inhibitor” refers to a compound that hasa biological effect to inhibit or significantly reduce or down-regulatethe expression of the gene encoding for IDO1 and/or the expression ofIDO1 and/or the biological activity of IDO1.

“D” and “d” both refer to deuterium. “dx.y” refers to substitution withfrom x to y number of deuterium atoms. “Stereoisomer” refers to bothenantiomers and diastereomers. A group is “substituted with” asubstituent when one or more hydrogen atoms of the group are replacedwith a corresponding number of substituent atoms (if the substituent isan atom) or groups (if the substituent is a group). For example,“substituted with deuterium” refers to the replacement of one or morehydrogen atoms with a corresponding number of deuterium atoms.

The words “comprise”, “comprises”, and “comprising” are to beinterpreted inclusively rather than exclusively. The works “consist”,“consisting”, and its variants, are to be interpreted exclusively,rather than inclusively.

As used herein, the term “about” means a variability of 10% from thereference given, unless otherwise specified.

EXAMPLES

The present invention will be better understood with reference to thefollowing examples. These examples are intended to representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

I. Chemistry Examples

The MS data provided in the examples described below were obtained asfollowed: Mass spectrum: LC/MS Agilent 6110 (ESI) or a Waters AcquitySQD (ESI)

The NMR data provided in the examples described below were obtained asfollowed: Bruker Ultrashield™ 400 PLUS and Bruker Fourier 300 MHz andTMS was used as an internal standard.

The microwave chemistry was performed on a single mode microwave reactorInitiator Microwave System EU from Biotage.

Preparative HPLC purifications were performed with a mass directedautopurification Fractionlynx from Waters equipped with a Xbridge™ PrepC18 OBD column 19×150 mm 5 μm, unless otherwise reported. All HPLCpurifications were performed with a gradient of CH₃CN/H₂O/NH₄HCO₃ (5mM), CH₃CN/H₂O/TFA (0.1%), or CH₃CN/H₂O/NH₃H₂O (0.1%).

Compound 1: 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

A. Route A

A mixture of 5-fluoro-1H-indole (300 mg; 2.22 mmol), maleimide (646 mg;6.65 mmol) in AcOH (2 mL) was stirred at 170° C. for 2 h in a microwavereaction. The reaction mixture was concentrated in vacuo. The residuewas neutralized with saturated aqueous NaHCO₃ solution to pH 7-8 andextracted with EtOAc (10 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered, concentrated, and purified bypreparative HPLC to afford 180 mg (35%) of the title compound as ayellow solid. LC-MS for C₁₂H₆FN₂O₂−H⁻[M−H]: calcd. 231.1. found: 231.0.¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.30 (brs, 1H), 11.14 (s, 1H), 7.41(d, J=2.5 Hz, 1H), 7.36 (dd, J=9.0, 4.6 Hz, 1H), 7.20 (dd, J=10.1, 2.5Hz, 1H), 6.94 (ddd, J=9.2, 9.0, 2.5 Hz, 1H), 4.33 (dd, J=9.5, 5.5 Hz,1H), 3.17 (dd, J=18.0, 9.5 Hz, 1H), 2.79 (dd, J=18.0, 5.5 Hz, 1H).

Route B:

Alternatively, a mixture of 5-Fluoroindole (5.00 g, 5.00 g, 35.5 mmol,96 mass %, 1.00) and Maleimide (1.5 equiv., 5.17 g, 53.3 mmol, 1.50) wascharged in a 50 mL vessel, and then Acetonitrile (3 L/kg, 15.0 mL, 11.7g, 286 mmol, 100 mass %) and Zinc Chloride (1.05 equiv., 5.08 g, 37.3mmol, 100 mass %) were added. The reaction was heated to 85° C. over 10min and then maintained at 85° C. for 24 hrs. While still at 85° C.,Water (6 L/kg, 30.0 mL, 30.0 g, 1670 mmol, 100 mass %) was added slowly,while maintaining the temperature above 80° C. Yellow solidsprecipitated. The reaction mixture was cooled to 50° C. over 1 hourfollowed by stirring at 50° C. for 2 hours, then cooled 10° C. over 1hour. The reaction was stirred at 10° C. for 1 hour. The solids werefiltered off, then the filter cake was washed 2 times with 5 ml 1:1ACN/water to afford isolated compound (6.85 g, 6.85 g, 29.5 mmol, 83.1%Yield).

For purification, the resulting isolated compound was charged (6.85 g,6.85 g, 29.5 mmol, 100 mass %) into a vessel, followed by addition ofTetrahydrofuran (6 L/kg, 41.1 mL, 36.4 g, 505 mmol, 100 mass %). Thismixture was heated to 66° C. to form a homogeneous solution. Heptane (4L/kg, 27.4 mL, 18.7 g, 187 mmol, 100 mass %, was added slowly at 66° C.;solids began to precipitate after 5 volumes. The mixture was cooled to25° C. over 3 hours, then filtered and washed with heptane, followed bydrying in the high vacuum oven overnight. Isolated compound (4.93 g,4.93 g, 21.2 mmol, 100 mass %, 72.0% Yield).

This isolated compound is charged 2 (1.00 g, 4.3 mmol, 100 mass %) intoa 50 ml vessel And Tetrahydrofuran (6 L/kg, 6 mL, 100 mass %) andHeptane (6 L/kg, 6 mL, 100 mass %) were added. The slurry was stirred at25° C. for 48 hrs. The solids were filtered off and dried in the highvacuum oven overnight. The Isolated compound: (0.89 g, 0.89 g, 3.83mmol, 100 mass %, 89.00% Yield).

Compound 1a: (3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

To a solution of 3-(5-Fluoro-1H-indol-3-yl)-pyrrolidine-2,5-dione(Compound 1, 200 mg, 0.87 mmol) in D₂O (3 mL) was added K₂CO₃ (300 mg,2.2 mmol). The reaction was stirred at 40° C. overnight. The mixture wasextracted with EtOAc. The organic layer was dried, filtered,concentrated and purified by preparative HPLC to afford the TitleCompound (20 mg, 10%) as a yellow solid. LC-MS for C₁₂H₈DFN₂O₂−H⁻[M−H]⁻: calcd. 232.1. found: 232.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]:11.28 (s, 1H), 11.15 (s, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.36 (dd, J=8.7,4.5 Hz, 1H), 7.20 (dd, J=10.2, 2.4 Hz, 1H), 6.97-6.90 (m, 1H), 3.19-3.13(m, 1H), 2.80-2.74 (m, 1H).

Compound 2: (−)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

50 mg of the title compound was obtained as a yellow solid by chiralpreparative HPLC separation of 150 mg of compound 1. Preparative chiralHPLC: Chiralpak® AS-H 250 mm×20 mm 5 μm; Mobile phase: CO₂/IPA=60/40;Flow: 50 mL/min 214 nm ambient temperature. Analytical chiral HPLC:Chiralpak® IC 250 mm×4.6 mm 5 μm; Mobile phase: Hexane/EtOH=70/30; Flow:1.0 mL/min 230 nm ambient temperature; Retention time: 6.25 min. P1:96.3% e.e. [α]²⁵⁴ _(D)=−75.4 (c=0.0014, MeOH). LC-MS for C₁₂H₉FN₂O₂+H⁺[M+H]⁺: calcd. 233.1. found: 233.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]:11.30 (brs, 1H), 11.14 (s, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.36 (dd, J=9.0,4.6 Hz, 1H), 7.20 (dd, J=10.1, 2.5 Hz, 1H), 6.94 (ddd, J=9.2, 9.0, 2.5Hz, 1H), 4.33 (dd, J=9.5, 5.5 Hz, 1H), 3.17 (dd, J=18.0, 9.5 Hz, 1H),2.79 (dd, J=18.0, 5.5 Hz, 1H).

Compound 2a: (+)-(S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral separationdescribed for Compound 2a. Chiral HPLC retention time: 6.96 min. 98.5%e.e. [α]²⁵⁴ _(D)=70 (c=0.0014, MeOH).

Compound 3: 3-(1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from1H-indole (2.00 g; 17.1 mmol) and maleimide (4.96 g; 51.1 mmol), 2.50 g(68%) of the title compound was obtained as a yellow solid afterpurification by silica gel chromatography (petroleum ether/EtOAc=1/1).LC-MS for C₁₂H₁₀FN₂O₂+H⁺ [M+H]⁺: calcd. 215.1. found: 215.1. ¹H NMR (400MHz, DMSO-d₆) δ [ppm]: 11.29 (s, 1H), 11.02 (s, 1H), 7.42 (d, J=8.0 Hz,1H), 7.39 (d, J=8.1 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 7.12-7.07 (m, 1H),7.02-6.97 (m, 1H), 4.33 (dd, J=9.5, 5.3 Hz, 1H), 3.18 (dd, J=18.0, 9.5Hz, 1H), 2.76 (dd, J=18.0, 5.3 Hz, 1H).

Compound 4: (−)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione

100 mg of the title compound was obtained as a yellow solid by chiralpreparative HPLC separation of 250 mg of compound 3. Preparative chiralHPLC: Chiralcel OJ-H 250 mm×4.6 mm 5 μm; Mobile phase: CO₂/MeOH=60/40;Flow: 50 mL/min 230 nm ambient temperature. Analytical chiral HPLC:Chiralcel IC 250 mm×4.6 mm 5 μm; Mobile phase: Hexane/EtOH=70/30; Flow:1.0 mL/min 230 nm ambient temperature; Retention time: 7.632 min. P1:99.7% e.e. [α]²⁵⁴ _(D)=−64.6 (c=0.01, MeOH). LC-MS for C₁₂H₁₀FN₂O₂+H⁺[M+H]⁺: calcd. 215.1. found: 215.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]:11.29 (s, 1H), 11.02 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.1 Hz,1H), 7.32 (d, J=2.4 Hz, 1H), 7.12-7.07 (m, 1H), 7.02-6.97 (m, 1H), 4.33(dd, J=9.5, 5.3 Hz, 1H), 3.18 (dd, J=18.0, 9.5 Hz, 1H), 2.76 (dd,J=18.0, 5.3 Hz, 1H).

Compound 4a: (+)-(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral separationdescribed for Compound 4a. Chiral HPLC retention time: 9.028 min. 99.6%e.e. [α]²⁵⁴ _(D)=64.5 (c=0.01, MeOH).

Compound 5: 3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from5-chloro-1H-indole (2.00 g; 13.2 mmol) and maleimide (3.84 g; 39.6mmol), 160 mg (4.9%) of the title compound was obtained as a yellowsolid after purification by silica gel chromatography (petroleumether/EtOAc=3/1). LC-MS for C₁₂H₉ClN₂O₂−H⁻ [M−H]⁻: calcd. 247.0. found:247.0. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.30 (br s, 1H), 11.25 (br s,1H), 7.49 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.6 Hz,1H), 7.10 (dd, J=8.6, 2.0 Hz, 1H), 4.36 (dd, J=9.5, 5.5 Hz, 1H), 3.17(dd, J=18.0, 9.5 Hz, 1H), 2.80 (dd, J=18.0, 5.5 Hz, 1H).

Compound 6: (−)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione

25 mg of the title compound was obtained by chiral preparative HPLCseparation of 120 mg of compound 5. Preparative chiral HPLC: Chiralpak®IC 250 mm×20 mm 5 μm; Mobile phase: Hexane/EtOH=70/30; Flow: 15 mL/min214 nm ambient temperature. Analytical chiral HPLC: Chiralpak® IC 250mm×4.6 mm 5 μm; Mobile phase: Hexane/EtOH=70/30; Flow: 1.0 mL/min 230 nmambient temperature; Retention time: 6.073 min. P1: 99.5% e.e. [α]²⁵⁴_(D)=−69.0 (c=0.0042, MeOH). LC-MS for C₁₂H₉ClN₂O₂+H⁺ [M+H]⁺: calcd.249.0. found: 249.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.29 (br s,1H), 11.25 (br s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H),7.39 (d, J=8.6 Hz, 1H), 7.10 (dd, J=8.6, 2.0 Hz, 1H), 4.36 (dd, J=9.5,5.5 Hz, 1H), 3.17 (dd, J=18.0, 9.5 Hz, 1H), 2.80 (dd, J=18.0, 5.5 Hz,1H).

Compound 6a: (+)-(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral separationdescribed for Compound 6a. Chiral HPLC retention time: 6.868 min. P1:99.6% e.e. [α]²⁵⁴ _(D)=67.4 (c=0.0038, MeOH).

Compound 7: 3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-chloro-5-fluoro-1H-indole (300 mg; 1.77 mmol) and maleimide (513 mg;5.28 mmol), 110 mg (23%) of the title compound was obtained as a yellowsolid after purification by preparative HPLC. LC-MS for C₁₂H₈ClFN₂O₂−H⁻[M−H]⁻: calcd. 265.1. found: 265.0. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]:11.30 (br s, 1H), 11.27 (br s, 1H), 7.54 (d, J=6.4 Hz, 1H), 7.47 (s,1H), 7.46 (d, J=10.2 Hz, 1H), 4.35 (dd, J=9.4, 5.8 Hz, 1H), 3.16 (dd,J=18.0, 9.4 Hz, 1H), 2.81 (dd, J=18.0, 5.8 Hz, 1H).

Compound 8: (R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

25 mg of the title compound was obtained by chiral preparative HPLCseparation of 70 mg of compound 7. Preparative chiral HPLC: Chiralpak®AS-H 250 mm×20 mm 5 μm; Mobile phase: CO₂/IPA=60/40; Flow: 50 mL/min 220nm ambient temperature. Analytical chiral HPLC: Chiralpak® IA 250 mm×4.6mm 5 μm; Mobile phase: CO₂/IPA/DEA=70/30/0.2; Flow: 1.0 mL/min 230 nmambient temperature; Retention time: 3.72 min. P1: >99.5% e.e. LC-MS forC₁₂H₈ClFN₂O₂−H⁻ [M−H]⁻: calcd. 265.1. found: 265.1. ¹H NMR (300 MHz,DMSO-d₆) δ [ppm]: 11.30 (br s, 1H), 11.27 (br s, 1H), 7.54 (d, J=6.4 Hz,1H), 7.47 (s, 1H), 7.46 (d, J=10.2 Hz, 1H), 4.35 (dd, J=9.4, 5.8 Hz,1H), 3.16 (dd, J=18.0, 9.4 Hz, 1H), 2.81 (dd, J=18.0, 5.8 Hz, 1H).

Compound 8a:(S)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral separationdescribed for Compound 8a. Chiral HPLC retention time: 5.48 min. 99.6%e.e.

Compound 9: 3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-bromo-5-fluoro-1H-indole (213 mg; 1.00 mmol) and maleimide (388 mg;4.00 mmol), 70 mg (23%) of the title compound was obtained as a yellowsolid after purification by preparative HPLC. LC-MS for C₁₂H₈BrFN₂O₂−H⁻[M−H]⁻: calcd. 309.0. found: 308.9. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]:11.31 (s, 1H), 11.27 (s, 1H), 7.66 (d, J=6.0 Hz, 1H), 7.48 (d, J=1.7 Hz,1H), 7.44 (d, J=9.8 Hz, 1H), 4.36 (dd, J=9.2, 5.6 Hz, 1H), 3.17 (dd,J=18.0, 9.2 Hz, 1H), 2.82 (dd, J=18.0, 5.6 Hz, 1H).

Compound 10: (R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

22 mg of the title compound was obtained by chiral preparative HPLCseparation of 60 mg of compound 9. Preparative chiral HPLC: Chiralpak®AD-H 250 mm×20 mm 5 μm; Mobile phase: CO₂/MeOH=60/40; Flow: 50 mL/min214 nm ambient temperature. Analytical chiral HPLC: Chiralpak® ID 250mm×4.6 mm 5 μm; Mobile phase: CO₂/MeOH=60/40; Flow: 3.0 mL/min 230 nmambient temperature; Retention time: 2.14 min. P1: >99.5% e.e. LC-MS forC₁₂H₈BrFN₂O₂−H⁻ [M−H]⁻: calcd. 309.0. found: 308.8. ¹H NMR (300 MHz,DMSO-d₆) δ [ppm]: 11.31 (s, 1H), 11.27 (s, 1H), 7.66 (d, J=6.0 Hz, 1H),7.48 (d, J=1.7 Hz, 1H), 7.44 (d, J=9.8 Hz, 1H), 4.36 (dd, J=9.2, 5.6 Hz,1H), 3.17 (dd, J=18.0, 9.2 Hz, 1H), 2.82 (dd, J=18.0, 5.6 Hz, 1H).

Compound 10a:(S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Isolated as second-eluting enantiomer from the chiral separationdescribed for Compound 10a. Chiral HPLC retention time: 4.20 min. 98.9%e.e.

Compound 11: 3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from5-bromo-1H-indole (500 mg; 2.56 mmol) and maleimide (666 mg; 6.86 mmol),160 mg (21%) of the title compound was obtained as a yellow solid afterpurification by preparative HPLC. LC-MS for C₁₂H₆BrN₂O₂+H⁺ [M+H]⁺:calcd. 293.0. found: 293.0. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.29 (s,1H), 11.26 (s, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.35(d, J=8.6 Hz, 1H), 7.21 (dd, J=8.6, 1.8 Hz, 1H), 4.36 (dd, J=9.5, 5.5Hz, 1H), 3.17 (dd, J=18.0, 9.5 Hz, 1H), 2.80 (dd, J=18.0, 5.5 Hz, 1H).

Compound 12: 3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from5-methyl-1H-indole (300 mg; 2.29 mmol) and maleimide (670 mg; 6.87mmol), 200 mg (38%) of the title compound was obtained as a yellow solidafter recrystallization in MeOH. LC-MS for C₁₃H₁₂N₂O₂+H⁺ [M+H]⁺: calcd.229.1. found: 229.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.27 (s, 1H),10.88 (s, 1H), 7.26 (dd, J=8.3, 2.0 Hz), 7.25 (d, J=2.0 Hz, 1H), 7.19(s, 1H), 6.92 (d, J=8.3 Hz, 1H), 4.29 (dd, J=9.5, 5.3 Hz, 1H), 3.16 (dd,J=18.0, 9.5 Hz, 1H), 2.74 (dd, J=18.0, 5.3 Hz, 1H), 2.36 (s, 3H).

Compound 13: 3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from5-methoxy-1H-indole (200 mg; 1.36 mmol) and maleimide (407 mg; 4.19mmol), 170 mg (51%) of the title compound was obtained as a yellow solidafter purification by preparative HPLC. LC-MS for C₁₃H₁₂N₂O₃+H⁺ [M+H]⁺:calcd. 245.1. found: 245.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.25(brs, 1H), 10.86 (s, 1H), 7.27 (d, J=2.2 Hz 1H), 7.26 (d, J=8.6 Hz, 1H),6.91 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.6, 2.2 Hz, 1H), 4.30 (dd, J=9.6,5.3 Hz, 1H), 3.74 (s, 3H), 3.18 (dd, J=17.9, 9.6 Hz, 1H), 2.75 (dd,J=17.9, 5.3 Hz, 1H).

Compound 14: 3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile

A mixture of 3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione (compound11; 500 mg; 1.71 mmol) and CuCN (231 mg; 2.58 mmol) in NMP (3 mL) wasstirred at 200° C. for 1.5 h in a microwave reactor. The reactionmixture was purified by preparative HPLC to afford 110 mg (27%) of thetitle compound as a green solid. LC-MS for C₁₃H₉N₃O₂+H⁺ [M+H]⁺: calcd.240.1. found: 240.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.63 (brs, 1H),8.04 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.45 (dd,J=8.6, 1.8 Hz, 1H), 4.44 (dd, J=9.5, 5.8 Hz, 1H), 3.18 (dd, J=17.8, 9.5Hz, 1H), 2.87 (dd, J=17.8, 5.8 Hz, 1H).

Compound 15: 3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from5,6-difluoro-1H-indole (200 mg; 1.31 mmol) and maleimide (380 mg; 3.91mmol), 15 mg (5%) of the title compound was obtained as a yellow solidafter purification by preparative HPLC. LC-MS for C₁₂H₈F₂N₂O₂+H⁺ [M+H]⁺:calcd. 251.1. found: 251.0. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.27(brs, 1H), 11.21 (brs, 1H), 7.45 (dd, J=11.5, 8.0 Hz, 1H), 7.41 (d,J=1.8 Hz, 1H), 7.37 (dd, J=11.2, 7.0 Hz, 1H), 7.48-7.34 (m, 3H), 4.34(dd, J=9.3, 5.6 Hz, 1H), 3.16 (dd, J=18.0, 9.3 Hz, 1H), 2.80 (dd,J=18.0, 5.6 Hz, 1H).

Compound 16: 3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from5-fluoro-6-methyl-1H-indole (1.00 g; 6.70 mmol) and maleimide (2.10 g;21.6 mmol), 4.2 mg (0.2%) of the title compound was obtained as a yellowsolid after purification by preparative HPLC. LC-MS for C₁₃H₁₁FN₂O₂+H⁺[M+H]⁺: calcd. 247.1. found: 247.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]:11.28 (s, 1H), 10.99 (s, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.22 (d, J=6.4 Hz,1H), 7.13 (d, J=10.8 Hz, 1H), 4.29 (dd, J=9.4, 5.4 Hz, 1H), 3.16 (dd,J=18.0, 9.4 Hz, 1H), 2.76 (dd, J=18.0, 5.4 Hz, 1H), 2.30 (d, J=1.6 Hz,3H).

Compound 17: 3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-fluoro-1H-indole (4.00 g; 29.6 mmol) and maleimide (8.80 g; 90.7mmol), 3.0 g (44%) of the title compound was obtained as an orange solidafter purification by silica gel chromatography (petroleumether/EtOAc=3/1-2/3). LC-MS for C₁₂H₉FN₂O₂−H⁻ [M−H]⁻: calcd. 231.1.found: 231.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.10 (s, 1H), 7.43(dd, J=8.7, 5.4 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.14 (dd, J=10.1, 2.3Hz, 1H), 6.87 (td, J=9.8, 8.7, 2.3 Hz, 1H), 4.34 (dd, J=9.5, 5.4 Hz,1H), 3.17 (dd, J=18.0, 9.5 Hz, 1H), 2.77 (dd, J=18.0, 5.4 Hz, 1H).

Compound 18: 3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-chloro-1H-indole (0.50 g; 3.3 mmol) and maleimide (0.96 g; 9.9 mmol),100 mg (12%) of the title compound was obtained as a yellow solid afterpurification by silica gel chromatography (petroleum ether/EtOAc=5/1).LC-MS for C₁₂H₉ClN₂O₂−H⁻ [M−H]⁻: calcd. 247.0. found: 247.0. ¹H NMR (300MHz, DMSO-d₆) δ [ppm]: 11.27 (brs, 1H), 11.17 (s, 1H), 7.45 (d, J=8.4Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.03 (dd,J=8.4, 1.8 Hz, 1H), 4.34 (dd, J=9.5, 5.5 Hz, 1H), 3.17 (dd, J=18.0, 9.5Hz, 1H), 2.77 (dd, J=18.0, 5.5 Hz, 1H).

Compound 19: 3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-bromo-1H-indole (2.00 g; 10.2 mmol) and maleimide (2.96 g; 30.5 mmol),1.5 g (50%) of the title compound was obtained as a yellow solid afterpurification by preparative HPLC. LC-MS for C₁₂H₉BrN₂O₂+H⁺ [M+H]⁺:calcd. 293.0. found: 293.0. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.30(brs, 1H), 11.18 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.41 (d, J=8.5 Hz,1H), 7.37 (d, J=2.4 Hz, 1H), 7.14 (dd, J=8.5, 1.7 Hz, 1H), 4.34 (dd,J=9.5, 5.4 Hz, 1H), 3.17 (dd, J=18.0, 9.5 Hz, 1H), 2.77 (dd, J=18.0, 5.4Hz, 1H).

Compound 20: 3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-methyl-1H-indole (0.20 g; 1.52 mmol) and maleimide (0.44 g; 4.53mmol), 0.22 g (63%) of the title compound was obtained as a yellow solidafter purification by preparative HPLC. LC-MS for C₁₃H₁₂N₂O₂−H⁻ [M−H]⁻:calcd. 227.1. found: 227.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 10.85(brs, 2H), 11.18 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.20 (d, J=2.3 Hz,1H), 7.16 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.28 (dd, J=9.5, 5.3 Hz, 1H),3.17 (dd, J=18.0, 9.5 Hz, 1H), 2.73 (dd, J=18.0, 5.3 Hz, 1H), 2.38 (s,3H).

Compound 21: 3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione

Following the general method as outlined for compound 1, starting from6-methoxy-1H-indole (0.20 g; 1.36 mmol) and maleimide (0.40 g; 4.12mmol), 80 mg (24%) of the title compound was obtained as a yellow solidafter purification by preparative HPLC. LC-MS for C₁₃H₁₂N₂O₃−H⁻ [M−H]⁻:calcd. 243.1. found: 243.1. ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 11.26 (s,1H), 10.81 (s, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 6.86(d, J=2.2 Hz, 1H), 6.66 (dd, J=8.7, 2.2 Hz, 1H), 4.27 (dd, J=9.5, 5.2Hz, 1H), 3.75 (s, 3H), 3.16 (dd, J=18.0, 9.5 Hz, 1H), 2.73 (dd, J=18.0,5.2 Hz, 1H).

Compound 22: 3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile

Following the general method as outlined for compound 14, starting from3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione (compound 19; 0.20 g;0.68 mmol) and CuCN (90 mg; 1.00 mmol), 14 mg (8.6%) of the titlecompound was obtained as a yellow solid after purification bypreparative HPLC. LC-MS for C₁₃H₆N₃O₂+H⁺ [M+H]⁺: calcd. 240.1. found:240.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.63 (brs, 1H), 11.32 (s,1H), 7.88 (s, 1H), 7.68-7.62 (m, 2H), 7.35 (dd, J=9.5, 5.6 Hz, 1H), 4.42(dd, J=17.8, 9.5 Hz, 1H), 3.18 (dd, J=18.0, 9.9 Hz, 1H), 2.82 (dd,J=17.8, 5.6 Hz, 1H).

Compound 23: 3-(naphthalen-1-yl)pyrrolidine-2,5-dione

To a solution of naphthalen-1-ylboronic acid (0.27 g; 1.57 mmol) in1,4-dioxane (9 mL) and water (1.4 mL) was added Et₃N (0.10 g; 0.99mmol), [RhOH(cod)]₂ (23 mg; 0.05 mmol) and maleimide (100 mg; 1.03mmol). The dark brown mixture was heated at 50° C. for 2.5 h, cooled toroom temperature, and concentrated in vacuo. The residue was dilutedwith H₂O (10 mL) and extracted with DCM (20 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered, concentrated, andpurified by preparative HPLC to afford 136 mg (59%) of the titlecompound as a white solid. LC-MS for C₁₄H₁₁NO₂−H⁻ [M−H]⁻: calcd. 224.1.found: 224.1. ¹H NMR (300 MHz, DMSO-d₆) δ [ppm]: 11.50 (s, 1H),8.02-7.95 (m, 2H), 7.89 (d, J=9.1 Hz, 1H), 7.63-7.53 (m, 2H), 7.53-7.46(m, 1H), 7.41 (d, J=7.1 Hz, 1H), 4.96 (dd, J=9.6, 5.7 Hz, 1H), 3.32 (dd,J=18.0, 9.6 Hz, 1H), 2.71 (dd, J=18.0, 5.7 Hz, 1H).

Compound 24: 3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione

Step 1: 6-fluoronaphthalene-1-diazonium tetrafluoroborate

To a solution of 6-fluoronaphthalen-1-amine (500 mg; 3.10 mmol) and HBF₄(40%; 2 mL; 12.6 mmol) in H₂O (2 mL) at 0° C. was added a cold solutionof NaNO₂ (214 mg; 3.10 mmol) in H₂O (0.5 mL) dropwise. The reaction wasstirred at room temperature for 1 h. The precipitate was collected byfiltration, washed with EtOH (5 mL), Et₂O (5 mL), and dried under vacuumto afford 0.40 g (50%) of the title compound as a pale solid, which wasused to directly in the next step without further purification.

Step 2: 2-(6-fluoronaphthalen-1-yl)succinic acid

Maleic anhydride (150 mg; 1.54 mmol) was added with to an aqueous NaOHsolution (4 M; 0.70 mL; 2.8 mmol). The resulting solution was added at0-5° C. to an aqueous TiCl₃ solution (15%; 3.2 g; 3.11 mmol), followedby acetone (2 mL). The cooling bath was removed and6-fluoronaphthalene-1-diazonium tetrafluoroborate (Step 1: 400 mg; 1.54mmol) was added slowly over 0.7 h. The suspension was stirred at roomtemperature for 1.5 h, concentrated to remove acetone, and extractedwith Et₂O (10 mL×3). The aqueous layer was acidified to pH-1 with HCl (1M) and extracted with EtOAc (10 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered, and concentrated to afford 190 mg(47%) of the title compound as a brown solid, which was used directly inthe next step without further purification. LC-MS for C₁₄H₁₁FO₄+NH₄⁺×[M+NH₄]⁺: calcd. 280.1. found: 280.0.

Step 3

A mixture of 2-(6-fluoronaphthalen-1-yl)succinic acid (190 mg; 0.72mmol) and urea (170 mg; 2.83 mmol) was stirred at 180° C. for 1 h. Thereaction mixture was purified by silica gel chromatography (petroleumether/EtOAc=1/1) to give a yellow solid, which was further purified bypreparative HPLC to afford 63 mg (36%) the title compound as a whitesolid. LC-MS for C₁₄H₁₀FNO₂+H⁺ [M+H]⁺: calcd. 244.1. found: 243.9. ¹HNMR (300 MHz, DMSO-d₆) δ [ppm]: 8.08 (dd, J=9.3, 5.6 Hz, 1H), 7.87 (d,J=8.2 Hz, 1H), 7.76 (dd, J=10.2, 2.7 Hz, 1H), 7.56-7.46 (m, 2H), 7.38(d, J=6.6 Hz, 1H), 4.95 (dd, J=9.4, 5.6 Hz, 1H), 3.30 (dd, J=18.0, 9.4Hz, 1H), 2.71 (dd, J=18.0, 5.6 Hz, 1H).

Compound 25: 3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione

Step 1: 7-fluoronaphthalene-1-diazonium tetrafluoroborate

Following the general method as outlined for compound 24—Step 1,starting from 7-fluoronaphthalen-1-amine (300 mg; 1.86 mmol), HBF₄ (40%;1.5 mL; 9.4 mmol), H₂O (5 mL), NaNO₂ (260 mg; 3.77 mmol) in H₂O (4 mL),300 mg (62%) of the title compound was obtained as a pale solid, whichwas used to directly in the next step without further purification.LC-MS for C₁₀H₆FN₂ ⁺ [M]⁺: calcd. 173.1. found: 173.0.

Step 2: 2-(7-fluoronaphthalen-1-yl)succinic acid

Following the general method as outlined for compound 24—Step 2,starting from maleic anhydride (110 mg; 1.12 mmol), aqueous NaOHsolution (4 M; 0.7 mL; 2.8 mmol), aqueous TiCl₃ solution (15%; 2.36 g;2.32 mmol), acetone (2 mL), and 7-fluoronaphthalene-1-diazoniumtetrafluoroborate (Step 1: 300 mg; 1.15 mmol), 200 mg (66%) of the titlecompound was obtained as a brown solid, which was used directly in thenext step without further purification.

Step 3

Following the general method as outlined for compound 24—Step 3,starting from 2-(7-fluoronaphthalen-1-yl)succinic acid (Step 2; 200 mg;0.76 mmol) and urea (180 mg; 3.00 mmol), 3.3 mg (1.8%) of the titlecompound was obtained as a white solid after purification by silica gelchromatography (petroleum ether/EtOAc=1/1) and preparative HPLC. LC-MSfor C₁₄H₁₀FNO₂−H⁻ [M−H]⁻: calcd. 242.1. found: 242.0. ¹H NMR (300 MHz,MeOH-d₄) δ [ppm]: 7.99 (dd, J=9.0, 5.9 Hz, 1H), 7.88 (dd, J=6.8, 2.0 Hz,1H), 7.70 (d, J=11.1, 2.0 Hz, 2H), 7.50-7.42 (m, 1H), 7.41-7.32 (m, 1H),4.88 (dd, J=9.5, 5.1 Hz, 1H), 3.43 (dd, J=18.2, 9.5 Hz, 1H), 2.72 (dd,J=18.2, 5.1 Hz, 1H).

Compound 26: 3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione

Step 1: 6-chloronaphthalene-1-diazonium tetrafluoroborate

Following the general method as outlined for compound 24—Step 1,starting from 6-chloronaphthalen-1-amine (1.00 g; 5.63 mmol), HBF₄ (40%;4 mL; 25.2 mmol), H₂O (4 mL), and NaNO₂ (390 mg; 5.65 mmol) in H₂O (1mL), 1.50 g (96%) of the title compound as a purple solid, which wasused to directly in the next step without further purification. LC-MSfor C₁₀H₆ClN₂ ⁺ [M]⁺: calcd. 189.0. found: 188.9.

Step 2: 2-(6-chloronaphthalen-1-yl)succinic acid

Following the general method as outlined for compound 24—Step 2,starting from maleic anhydride (216 mg; 2.20 mmol), aqueous NaOHsolution (4 M; 6.0 mL; 24 mmol), aqueous TiCl₃ solution (15%; 4.5 g; 4.4mmol), acetone (2 mL), and 6-chloronaphthalene-1-diazoniumtetrafluoroborate (Step 1: 600 mg; 2.17 mmol), 600 mg (99%) of the titlecompound was obtained as a black solid, which was used directly in thenext step without further purification.

Step 3

Following the general method as outlined for compound 24—Step 3,starting from 2-(6-chloronaphthalen-1-yl)succinic acid (Step 2; 600 mg;2.15 mmol) and urea (600 mg; 9.99 mmol), 10 mg (2%) of the titlecompound was obtained as a yellow solid after purification by silica gelchromatography (petroleum ether/EtOAc=2/1) and preparative HPLC. LC-MSfor C₁₄H₁₀ClNO₂−H⁻ [M−H]⁻: calcd. 258.0. found: 257.9. ¹H NMR (400 MHz,MeOH-d₄) δ [ppm]: 8.02 (d, J=9.0 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.81(d, J=8.3 Hz, 1H), 7.57-7.49 (m, 2H), 7.42 (d, J=7.3 Hz, 1H), 4.96 (dd,J=9.8, 5.3 Hz, 1H), 3.44 (dd, J=18.3, 9.8 Hz, 1H), 2.77 (dd, J=18.2, 5.3Hz, 1H).

Compound 27: 3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione

Step 1: 7-chloronaphthalene-1-diazonium tetrafluoroborate

Following the general method as outlined for compound 24—Step 1,starting from 7-chloronaphthalen-1-amine (0.45 g; 2.53 mmol), HBF₄ (40%;2.5 mL; 15.7 mmol), H₂O (2 mL), and NaNO₂ (190 mg; 2.75 mmol) in H₂O (4mL), 400 mg (57%) of the title compound as a pale solid, which was usedto directly in the next step without further purification. LC-MS forC₁₀H₆ClN₂ ⁺ [M]⁺: calcd. 189.0. found: 188.9.

Step 2: 2-(7-chloronaphthalen-1-yl)succinic acid

Following the general method as outlined for compound 24—Step 2,starting from maleic anhydride (213 mg; 2.17 mmol), aqueous NaOHsolution (4 M; 0.7 mL; 2.8 mmol), aqueous TiCl₃ solution (15%; 4.46 g;4.3 mmol), acetone (2 mL), and 7-chloronaphthalene-1-diazoniumtetrafluoroborate (Step 1: 600 mg; 2.17 mmol), 500 mg (83%) of the titlecompound was obtained as a brown solid, which was used directly in thenext step without further purification.

Step 3

Following the general method as outlined for compound 24—Step 3,starting from 2-(7-chloronaphthalen-1-yl)succinic acid (Step 2; 500 mg;1.79 mmol) and urea (430 mg; 7.16 mmol), 2.5 mg (0.5%) of the titlecompound was obtained as a white solid after purification by silica gelchromatography (petroleum ether/EtOAc=1/1) and preparative HPLC. LC-MSfor C₁₄H₁₀ClNO₂+H⁺ [M+H]⁺: calcd. 260.0. found: 260.0. ¹H NMR (300 MHz,MeOH-d₄) δ [ppm]: 8.08 (s, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.59-7.53 (m, 3H), 4.94 (dd, J=9.6, 5.4 Hz, 1H), 3.44 (dd,J=18.3, 9.6 Hz, 1H), 2.75 (dd, J=18.3, 5.4 Hz, 1H).

II. Biology Examples II.1 Assay for IDO1 Enzymatic ActivityDetermination

The compounds of the present invention inhibit the enzymatic activity ofhuman IDO1.

To measure enzymatic activity of human IDO1, the reaction mixturecontained (final concentrations) potassium phosphate buffer (50 mM, pH6.5), ascorbic acid (10 mM), methylene blue (5 μM) and human recombinantIDO1 enzyme (prepared as described in Rohrig et al. J Med Chem, 2012,55, 5270-5290; final concentration 5 μg/mL) without or with thecompounds of the present invention at the indicated concentrations(total volume 112.5 μL). The reaction was initiated by the addition of37.5 μL of L-Trp (final concentration 100 μM) at room temperature. Thereaction was conducted at room temperature during 15 minutes and stoppedby the addition of 30 μL of 30% (w/v) trichloroacetic acid.

To convert N-formylkynurenine into kynurenine, the reaction mixture wasincubated at 65° C. for 30 min. Then 120 μL of 2.5% (w/v)4-(dimethylamino)-benzaldehyde in acetic acid were added and the mixtureincubated for 5 min at room temperature. Kynurenine concentrations weredetermined by measuring the absorbance at 480 nm. A standard curve wasmade with pure kynurenine. The IDO1 activity was measured as describedabove using ten serial concentrations of the compounds of the presentinvention. Data were fitted using the Prism software (GraphPad Software,Inc.).

The biological activity of representative compounds is summarized in thefollowing table:

Compound IC₅₀ (μM)  1 0.15  1a 0.21  2 0.12  2a >50  3 3.0  4 1.8 4a >50  5 2.1  6 2.2  6a >50  7 0.49  9 0.29 10 0.62  10a 8.0 11 0.3712 53 13 53 14 12 15 1.8 16 46 17 3.4 18 2.1 19 0.42 20 54 22 1.7 23 1824 1.7 25 4.6

In one embodiment, compounds with an IC50 below 5 μM are generallydesirable to be selected for further study.

II.2.A Cellular Assay for IDO Activity Determination: hIDO1 P815 Cells

The compounds of the present invention inhibit the activity of human IDOin hIDO1 P815 cells [(ATCC® TIB-64™), Mus musculus mastocytoma cell)],available from American Type Culture Collection (ATCC), Manassas Va.].

The assay was performed in 96-well flat bottom plates seeded with P815cells overexpressing hIDO1 (prepared as described in Rohrig et al. J MedChem, 2012, 55, 5270-5290), at a concentration of 2×10⁵ cells/well in afinal volume of 200 μL. To determine IDO1 activity, the cells wereincubated 24 hours at 37° C. at 5% CO₂ in IMDM (Invitrogen) supplementedwith 2% FBS and 2% penicillin/streptomycin in the presence of thecompounds of the present invention, at different concentrations.

The plates were then centrifuged 5 min at 1000 rpm, and 100 μL of thesupernatant were collected in a conical plate, 30 uL of TCA 30% wereadded and a further centrifugated at 3000×g for 10 minutes. 100 μL ofthe supernatant were collected in a flat bottomed plate and 100 μL of 2%(w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5min at room temperature. Kynurenine concentrations were determined bymeasuring the absorbance at 480 nm. A standard curve was made with purekynurenine. The IDO1 activity was measured as described above using tendifferent concentrations of the compounds of the present invention. Datawere fitted using the Prism software (GraphPad Software, Inc.).

The biological activity of representative compounds is summarized in thefollowing table:

Compound IC₅₀ (M)  1 0.094  2 0.009  2a 0.45  3 0.92  4 0.24  4a 3.30  50.59 15 0.26 18 0.50

In one embodiment, compounds with an IC50 below 5 μM are generallydesirable to be selected for further study.

II.2.B Cellular Assay for IDO1 Activity Determination: HeLa Cells

The compounds of the present invention inhibit the activity of humanIDO1 in HeLa cells [human adenocarcinoma Cells,® CCL-2™].

The assay was performed in 96-well flat bottom plates seeded with thehuman cervical cancer HeLa cell line with stimulation with IFN.

To adhere HeLa cells (concentration of 5×10³ cells/well) were incubatedovernight at 37° C. at 5% CO₂ in EMEM (Lonza) supplemented with 10% FBS,2% penicillin/streptomycin and 2 mM Ultraglutamin, in a final volume of200 μL.

To stimulate the expression of IDO1, cells were then incubated two daysat 37° C. at 5% CO₂ in EMEM (Lonza) supplemented with 2% FBS, 2%penicillin/streptomycin and 2 mM Ultraglutamine and 100 ng/mL IFNγ(R&D).

To determine IDO1 activity, medium was removed then the cells wereincubated one day at 37° C. at 5% CO₂ in EMEM (Lonza) supplemented with2% FBS and 2% penicillin/streptomycin in the presence of the compoundsof the present invention, at different concentrations. Then 100 μL ofthe supernatant were collected in a conical plate, 30 uL of TCA 30% wereadded and a centrifugation was made at 3000×g for 10 minutes. 100 μL ofthe supernatant were collected in a flat bottom plate and 100 μL of 2%(w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5min at room temperature. Kynurenine concentrations were determined bymeasuring the absorbance at 480 nm. A standard curve was made with purekynurenine. Data were fitted using the Prism software (GraphPadSoftware, Inc.).

The biological activity of representative compounds is summarized in thefollowing table:

Compound IC₅₀ (μM) 1 1.0 2 0.77 6 3.4 8 3.6 9 7.0 11 5.9

In one embodiment, compounds with an IC50 below 5 μM are generallydesirable to be selected for further study.

II.2.C Assay for IDO1 Activity Determination in Human Blood: Whole BloodLeukocyte Concentrate

The compounds of the present invention inhibit the activity of humanIDO1 in a human whole blood assay (whole blood leukocyte concentrate).

The human whole blood leukocyte concentrate was obtained as a byproductin the manufacturing of red blood cell and platelet concentrate from awhole blood donation (as described in van der Meer et al., Vox Sang,1999, 76(2), 90-99).

The assay was performed in 96-well flat bottom plates containingundiluted human whole blood leukocyte concentrate (with 2%penicillin/streptomycin) stimulated with lipopolysaccharide (LPS) (12.5μg/mL) and recombinant human gamma interferon (rh IFNg) (50 ng/mL) for18 hours to induce conversion of tryptophan to kynurenine. Plasma wascollected after centrifugation and plasma kynurenine levels weredetermined LC-MS/MS (HPLC column Unison™ UK-Phenyl, 75×4.6, 3 μm, flowrate 0.8 mL/min, 4 minutes gradient from water+0.2% acetic acid tomethanol+0.1% formic acid, retention time 2.7 min; API 4000™ MS-MSsystem from AB Sciex, ESI+ mode, parent ion 209.2, daughter ion 94.1).

To determine the effect of IDO1 inhibition on kynurenine production, thecompounds of the present invention were co-incubated at differentconcentrations. Data were fitted using the Prism software (GraphPadSoftware, Inc.).

The biological activity of representative compounds is summarized in thefollowing table (results are the average of the results with blood fromseveral different donors):

IC₅₀ (μM) ± Number of individ- Compound Standard Deviation ual blooddonors 1 3.36 ± 0.51 13 2 3.26 ± 0.71 15

II.2.D Cellular Assay for IDO1-Dependent T Cell ProliferationDetermination: SKOV-3 PBMC Co-Culture

The compounds of the present invention restore T-cell proliferation in aSKOV-3 PBMC co-culture assay.

The assay was performed in 96-well flat bottom plates seeded with thehuman ovarian adenocarcinoma SKOV-3 cell line [SKOV-3; SKOV3] (ATCC®HTB-77™)] and co-cultured with human peripheral blood mononuclear cells(PBMC) stimulated with CD3/CD28 beads and rhIL-2.

To adhere, irradiated SKOV-3 cells (concentration of 150×10³ cells/well)were incubated overnight at 37° C. at 5% CO₂ in Iscove's ModifiedDulbecco's Medium (IMDM) (Lonza) supplemented with 50% FBS, 2%penicillin/streptomycin and 2 mM Ultraglutamin, in a final volume of 150μL. Isolated PBMCs (stimulated with CD3/CD28 beads and rhIL-2 (30 U/mL))were added in a ratio of 1:1. After 24 h of co-culture ³H-Thymidine (1μCurie/10 uL) was added to assess proliferation (TopCount counter,Perkin Elmer) after overnight incubation in the presence of 50% serum.

To determine the effect of IDO1 inhibition on restoration of T cellproliferation, the compounds of the present invention were co-incubatedat different concentrations.

Compound 2 showed an EC₅₀ of 0.074 μM in this assay (average of threeindependent experiments). FIG. 1 shows the effect of increasingconcentrations of Compound 2 on Thymidine incorporation.

II.3 In-Vivo Inhibition of Blood Kynurenine Levels in Healthy Mice

The compounds of the present invention reduce the amount of Kynureninein healthy mouse blood.

Briefly, mice were treated with either a suspension of one of thecompounds of the present invention in 0.5% hydroxypropyl methylcellulose(HPMC) K4M/0.25% Tween 20 at different doses, or with a vehicle control(0.5% HPMC K4M/0.25% Tween 20), by the oral route by gavage (dosingvolume 5 mL/kg, 10 mice per group). After two hours, blood washarvested, plasma was prepared and the amount of Kynurenine present wasdetermined by LC-MS-MS (HPLC column Unison UK-Phenyl, 75×4.6, 3 μm, flowrate 0.8 mL/min, 4 minutes gradient from water+0.2% acetic acid tomethanol+0.1% formic acid, retention time 2.7 min; API4000™ MS-MS systemfrom AB Sciex, ESI+ mode, parent ion 209.2, daughter ion 94.1).

Compound 1 inhibited circulating Kynurenine by 41% at 100 mg/kg(p<0.0001) and by 59% at 200 mg/kg (p<0.0001): see table below.

Cpd. 1 Cpd. 1 Vehicle 100 mg/kg 200 mg/kg Kynurenine concen- 187.6 ±17.8 111.1 ± 27.0 77.7 ± 9.2 tration in plasma ng/mL ng/mL ng/mL(average ± standard error of the mean)

Compound 2 inhibited circulating Kynurenine by 39% at 10 mg/kg(p<0.0001), by 55% at 30 mg/kg (p<0.0001) and by 68% at 100 mg/kg(p<0.0001): see table below and FIG. 2.

Cpd. 2 Cpd. 2 Cpd. 2 Vehicle 10 mg/kg 30 mg/kg 100 mg/kg Kynurenineconcen- 201 ± 15.7 122 ± 3.5 91.0 ± 4.4 64.0 ± 3.8 tration in plasmang/mL ng/mL ng/mL ng/mL (average ± standard error of the mean)

Example II.4 In Vivo Efficacy Studies in 4T1 Breast Cancer SyngeneicModel

In vivo efficacy studies for Compounds of the present invention wereperformed on 4T1 syngeneic tumor model of Balb/c mice implantedorthotopically in the mammary gland. One hundred thousand 4T1 breastcancer cells (ATCC® CRL-2539™)] were implanted orthotopically within themammary gland of 7 weeks old Balb/c mice (day 0). Animals wererandomized based on tumor size when tumor average reached 60 mm³(between day 7 and 11) into different treatment cohorts. The Compound ofthe present invention was administered orally twice per day(approximately at 9 am and 5 pm) starting the day of randomization. TheCompounds were suspended into Methocel™ cellulose ether vehicle andsonicated before oral administration to animals using gavage needles.Treatment was administered daily until the end of the study. Allexperimental animals were monitored for body weight changes twiceweekly. Tumor volume was measured twice a week by a caliper device andcalculated with the following formula: Tumor volume=0.5×(length×width²).Studies were terminated before tumor volumes reached 2000 mm. TGI (%tumor growth inhibition) was determined as

$\left( {1 - \left( \frac{{Tx} - {T\; 0}}{{Cx} - {C\; 0}} \right)} \right) \star 100.$

The table below and FIG. 3A show that Compound 1 inhibits 4T1 tumorgrowth in vivo.

Mean tumor volume TGI Treatment (mm³) on day 25 (Tumor growthinhibition) Vehicle Methocel 736.4   0% Compound 1 443.7 43.4% 100 mg/kgBID

Example II.5 In Vivo Efficacy Studies with PancO2 Pancreatic CancerSyngeneic Model

In vivo efficacy studies of the Compounds of the present invention wereperformed on PancO2 syngeneic tumor model of C57/B16 mice implantedsubcutaneously. Five millions PancO2 pancreas cancer cells wereimplanted subcutaneously to 7 weeks old C57/B16 mice (day 0). Animalswere randomized based on tumor size when tumor average reached 60 mm³(between day 10 and 12) into different treatment cohorts. The Compoundwas administered orally twice per day (approximately at 9 am and 5 pm)starting the day of randomization. The Compound was suspended intoMethocel vehicle and sonicated before oral administration to animalsusing gavage needles. Treatment was administered daily until the end ofthe study. All experimental animals were monitored for body weightchanges weekly. Tumor volume was measured weekly using a caliper deviceand calculated with the following formula: Tumorvolume=0.5×(length×width²). Studies were terminated before tumor volumesreached 2000 mm. TGI (% tumor growth inhibition) was determined as

$\left( {1 - \left( \frac{{Tx} - {T\; 0}}{{Cx} - {C\; 0}} \right)} \right) \star 100.$

The table below and FIG. 4 show that Compound 1 inhibits PancO2 tumorgrowth in vivo.

Mean tumor volume TGI Treatment (mm³) on day 42 (Tumor growthinhibition) Vehicle Methocel 598.2   0% Compound 1 457.0 26.2% 200 mg/kgBID

In a separate study performed under the same conditions, Compound 2 (100mg/kg BID) was studied. Methocel vehicle or 100 mg/kg of Compound 2 wasadministered orally twice per day (8 hours apart) starting the day ofrandomization. Compound 2 was resuspended into Methocel vehicle andsonicated before oral administration to animals using gavage needles.Treatment was administered daily until the end of the study. Tumorvolume was measured weekly using a caliper device and calculated withthe following formula: Tumor volume=0.5×(length×width²). Mice wereconsidered as dead when tumor size reached 400 mm³. The table below showthat Compound 2 inhibits PancO2 tumor growth in vivo. SEM refers tostandard error of measurement.

Mean tumor volume (mm³) +/− TGI +/− SEM Treatment SEM on day 55 (Tumorgrowth inhibition) Vehicle Methocel ® 677.6 +/− 39.2 0% Compound 2 -586.6 +/− 48.4 16.8% +/− 8.2 100 mg/kg BID

Example II.6 In Vivo Efficacy Studies on Inhibition of TryptophanDegradation in 4T1 Tumor Tissue

Compounds of this invention are capable of lowering kynurenineconcentration within mouse tumors, for example 4T1 syngeneic tumors ofBalb/c mice implanted orthotopically in the mammary gland. One hundredthousand 4T1 breast cancer cells were implanted orthotopically withinthe mammary gland of 7 weeks old Balb/c mice (day 0). Animals wererandomized based on tumor size when tumor average reached 60 mm³ (day 6)into different treatment cohorts (n=10/group). Animals were treated withMethocel vehicle from day 6 to 26 until tumors reached a size comprisedbetween 1500 and 2000 mm³. Compound 1 was suspended into Methocelvehicle and sonicated before oral administration to animals using gavageneedles. Methocel vehicle or 200 mg/kg of Compound 1 was administeredorally twice per day (approximately at 9 am and 5 pm) on day 26 and 27days. The next morning, treatment was administered and mice weresacrificed 4 h after Compound 1 administration. The tumor was removed,weighted and frozen on dry ice. Tumors were analyzed by LC/MS-MS forKynurenine concentration. Compound 1 reduced Kynurenine concentration by47% (p<0.0001): see Table below and FIG. 5.

Kynurenine concentration (ng/g tumor) Treatment Average ± SEM VehicleMethocel 787.5 ± 46.2 Compound 1 417.2 ± 55.7 200 mg/kg

Example II.7 In Vivo Efficacy Studies on Inhibition of TryptophanDegradation in CT26 Tumor Tissue

A. Compounds of this Invention are Capable of Lowering KynurenineConcentration within Mouse Tumors

In the present study, CT26 syngeneic tumors were implantedsubcutaneously in Balb-c mice. More particularly, Five hundred thousand(500,000) CT26 colon carcinoma cancer cells [CT26.WT, available from theATCC® CRL-2628™] were implanted subcutaneously in 7 weeks old Balb/cmice (day 0). Animals were randomized based on tumor size when tumoraverage reached 150 mm³ (day 11) into different treatment cohorts(n=10/group). Compound 1 was suspended into Methocel™ (methylcellulose)vehicle and sonicated before oral administration to animals using gavageneedles. Methocel vehicle or Compound 1 was administered orally twiceper day (approximately at 9 am and 5 pm) at 200 mg/kg for 2 days to themice, once the tumor reached a size comprised between 1500 and 2000 mm³.The next morning, treatment was administered and mice were sacrificed 2h after Compound 1 administration. The tumor was removed, weighted andfrozen on dry ice. Tumors were analyzed by LC/MS-MS for Kynurenineconcentration.

Compound 1 reduced Kynurenine concentration by 59% (p<0.0001): see Tablebelow and FIG. 6.

Kynurenine concentration (ng/g tumor) Treatment Average ± SEM VehicleMethocel 2124 ± 272 Compound 1 876 ± 68 200 mg/kg

B. Compound 1 Inhibits Tumor Growth In Vivo.

In a separate study, anti-tumor efficacy of IDO-1 inhibition was testedin the colon syngeneic mouse tumor model CT26 with a range of differenttreatment regimens. The model was essentially as described above, exceptthat 1×10⁶ cells in phosphate buffered saline (PBS) were implantedsubcutaneously in the flank of 8 week old Balb/c females on day 0 (10 ineach group). Mice were randomized into treatment groups (100 mg/kg BID,200 mg/kg BID or 600 mg/kg BID) based on tumor size on day 9 whentreatment started. The results are shown the following table and in FIG.7.

Dose % TGI % TGI % TGI Group mg/kg Schedule (D15) (D17) (D20) N Vehicle— BID — — — 10 Compound 100 BID 29 33 20 10 1 Compound 200 BID 38 41 3410 1 Compound 600 BID 36 51 38 10 1

At the highest dose of 600 mg/kg, BID a significant tumor growthinhibition (TGI) of up to 51%. At lower doses of 100 and 200 mg/kg BID,TGIs based on the group averages of tumor measurements are slightlylower and thus suggest a dose proportionality.

All publications cited in this specification and priority applicationsincluding U.S. Provisional Patent Application No. 61/996,976, filed May15, 2014, are incorporated herein by reference. While the invention hasbeen described with reference to particular embodiments, it will beappreciated that modifications can be made without departing from thespirit of the invention. Such modifications are intended to fall withinthe scope of the appended claims.

1. A pharmaceutical composition comprising a compound of Formula I′, acompound of Formula I″, or a mixture thereof:

or a pharmaceutically acceptable enantiomer, salt, solvate or prodrugthereof, wherein: X represents —NH— or —CQ²=CQ³-; Q² and Q³ eachindependently represent H or C1 to C6 alkyl; R¹ and R² eachindependently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6alkoxy; and at least one pharmaceutically acceptable carrier.
 2. Thepharmaceutical composition according to claim 1, wherein Q² and Q³ eachindependently represent H or methyl.
 3. The pharmaceutical compositionaccording to claim 1, wherein Q² and Q³ each are H.
 4. Thepharmaceutical composition according to claim 1, wherein R¹ and R² eachindependently represent H or halo.
 5. The pharmaceutical compositionaccording to claim 1, wherein the composition comprises a racemate whichcomprises approximately equal molar amounts of the compound of FormulaI′ and the compound of Formula I″.
 6. The pharmaceutical compositionaccording to claim 1, wherein the composition comprises different molaramounts of the compound of Formula I′ and the compound of Formula I″. 7.The pharmaceutical composition according to claim 6, wherein thecomposition comprises a mixture of the compound of Formula I′ and thecompound of Formula I″, wherein the composition comprises greater than50% of a compound of Formula I′.
 8. The pharmaceutical compositionaccording to claim 7, wherein the composition comprises at least 95% to100% of the compound of Formula I′.
 9. The pharmaceutical compositionaccording to claim 1, wherein the compound is of Formula I′ is selectedfrom the group consisting of: (a)(−)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (b)(−)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (c)(−)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (d)(R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; and (e)(R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or apharmaceutically acceptable salt or solvate of any of (a) to (e). 10.The pharmaceutical composition according to claim 1, which comprises aracemic mixture of a compound of Formula I′ and Formula I″, wherein theracemate is selected from the group consisting of: (i)3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (ii)3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (iii)3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (iv)3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (v)3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (vi)3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione; (vii)3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; (viii)3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione; (ix)3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile; (x)3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (xi)3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; (xii)3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (xiii)3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (xiv)3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione; (xv)3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione; (xvi)3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione; (xvii)3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile; (xviii)3-(naphthalen-1-yl)pyrrolidine-2,5-dione; (xix)3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione; (xx)3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione; (xxii)3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; or (xxiii)3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione.
 11. The pharmaceuticalcomposition according to claim 1, wherein at least one of the hydrogenatoms of the compound of Formula I′, one of the hydrogen atoms of thecompound of Formula I″, or a hydrogen atom in both the compound ofFormula I and the compound of Formula I″ are replaced with a deuteriumatom.
 12. The pharmaceutical composition according to claim 11, whereinthe compound of formula I″ is selected from the group consisting of:(a″) (S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (b″)(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (c″)(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (d″)(S)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; and (e″)(S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or apharmaceutically acceptable salt or solvate thereof.
 13. Thepharmaceutical composition according to claim 1, wherein the compound isa free base.
 14. The pharmaceutical composition according to claim 1,which is a salt.
 15. The pharmaceutical composition according to claim14, wherein the salt is selected from the group consisting of: analuminium, calcium, choline, potassium, sodium or zinc salt.
 16. Thepharmaceutical composition according to claim 1, which is a solvate. 17.The pharmaceutical composition according to claim 1 which is a prodrug.18. A compound of Formula I′ or I″

or a pharmaceutically acceptable salt, solvate or prodrug thereof,wherein X represents —NH— or —CQ²=CQ³-; Q² and Q³ each independentlyrepresent H or C1 to C6 alkyl; R¹ and R² each independently represent H,halo, cyano, C1 to C6 alkyl or C1 to C6 alkoxy.
 19. The compoundaccording to claim 18, wherein Q2 and Q3 each independently represent Hor methyl.
 20. The compound according to claim 18, wherein Q2 and Q3each represent H.
 21. The compound according to claim 18, wherein R¹ andR² each independently represent H or halo.
 22. The compound according toclaim 18, wherein at least one of the hydrogen atoms of the compound ofFormula I′ or the compound of Formula I″ is replaced with a deuteriumatom.
 23. The compound according to claim 18, wherein the compound ofFormula I′ is selected from the group consisting of: (a)(−)-(R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (b)(−)-(R)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (c)(−)-(R)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (d)(R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; and (e)(R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or apharmaceutically acceptable salt or solvate of any of (a) to (e). 24.The compound according to claim 18, wherein the compound of Formula I″is selected from the group consisting of: (a″)(S)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (b″)(S)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione; (c″)(S)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione; (d″)(S)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; and (e″)(S)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, or apharmaceutically acceptable salt or solvate of any of (a) to (e). 25.The compound according to claim 18, which is a free base.
 26. Thecompound according to claim 18, which is a salt.
 27. A deuteratedcompound having the Formula Ia′:

or a pharmaceutically acceptable enantiomer or salt thereof, wherein: Xrepresents —NH— or —CQ²=CQ³-; Q² and Q³ each independently represent Hor C1 to C6 alkyl; R¹ and R² each independently represent H, halo,cyano, C1 to C6 alkyl or C1 to C6 alkoxy.
 28. The deuterated compoundaccording to claim 27, wherein Q² and Q³ each independently represent Hor methyl.
 29. The deuterated compound according to claim 27, wherein Q²and Q³ each represent H.
 30. The deuterated compound according to claim27, wherein R¹ and R² each independently represent H or halo.
 31. Thedeuterated compound according to claim 27, wherein the compound ofFormula Ia, or the enantiomer thereof, is selected from the group of:(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(−)-(R)-(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(+)-(S)-(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;(−)-(R)-(3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;(+−)-(S)-(3-²H)-3-(1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;(−)-(R)-(3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;(+)-(S)-(3-²H)-3-(5-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(R)-(3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(S)-(3-²H)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(S)-(3-²H)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(5-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(5-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(5-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile;(3-²H)-3-(5,6-difluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(5-fluoro-6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-chloro-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-bromo-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-methyl-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-methoxy-1H-indol-3-yl)pyrrolidine-2,5-dione;(3-²H)-3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-6-carbonitrile;(3-²H)-3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;(3-²H)-3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione;(3-²H)-3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; and(3-²H)-3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione, or apharmaceutically acceptable salt or solvate thereof.
 32. The deuteratedcompound according to claim 27, wherein the compound is(3-²H)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione.
 33. Thedeuterated compound according to claim 27, which is a free base.
 34. Thedeuterated compound according to claim 27 which is a pharmaceuticallyacceptable salt.
 35. The deuterated compound according to claim 27 whichis a solvate.
 36. A compound of Formula Ib

or a pharmaceutically acceptable enantiomer, salt, solvate or prodrugthereof, wherein: X represents —NH— or —CQ²=CQ³-; Q² and Q³ eachindependently represent H or C1 to C6 alkyl; R^(1b) and R^(2b) eachindependently represent H, halo, cyano, C1 to C6 alkyl or C1 to C6alkoxy; under the condition that when X represents —NH—, R^(1b) andR^(2b) are not both H; when X represents —NH—, then R^(1b) and R^(2b)are not both F; and further provided that when X represents —CQ²=CQ³,then R^(1b) and R^(2b) are not both H.
 37. The compound according toclaim 36, wherein Q² and Q³ each independently represent H or methyl.38. The compound according to claim 36, wherein Q² and Q³ each representH.
 39. The compound according to claim 36, wherein R^(1b) and R^(2b) areindependently H or halo.
 40. The compound according to claim 36,selected from the group consisting of: (a)3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (b)(R)-3-(6-chloro-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (c)3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (d)(R)-3-(6-bromo-5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione; (e)3-(6-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione; (f)3-(7-fluoronaphthalen-1-yl)pyrrolidine-2,5-dione; (g)3-(6-chloronaphthalen-1-yl)pyrrolidine-2,5-dione; or (h)3-(7-chloronaphthalen-1-yl)pyrrolidine-2,5-dione, or a pharmaceuticallyacceptable salt or solvate thereof.
 41. The compound according to claim36 which is a free base.
 42. The compound according to claim 36 which isa salt.
 43. The compound according to claim 36 which is a solvate.
 44. Amethod of delivering an IDO inhibitor or treating cancer comprisingdelivering to a subject in need thereof a pharmaceutical compositionaccording to claim
 1. 45. The method according to claim 44, wherein thecancer is selected from malignant melanoma, acute myelogenous leukemia,pancreatic, colorectal, prostate, cervical, brain, endometrial andovarian cancers.
 46. A method of delivering an IDO inhibitor or treatingcancer comprising delivering to a subject a compound according to claim18.
 47. Process for manufacturing a compound according to claim 18,comprising: reacting maleimide with a compound of Formula (i) or (ib)

wherein and R^(1b) and R^(b) are as defined in claim 35; X represents—NH— or —CQ²=CQ³-; and R¹ and R² each independently represent H, halo,cyano, C1 to C6 alkyl or C1 to C6 alkoxy; and and optionally separatingenantiomers.
 48. A compound having the structure of Formula II′:

or a pharmaceutically acceptable salt or solvate thereof.
 49. Thecompound according to claim 48, wherein the compound is a free base. 50.A compound having the structure of Formula II″:

or a pharmaceutically acceptable salt thereof.
 51. The compoundaccording to claim 50, wherein the compound is a free base.
 52. Apharmaceutical composition comprising a compound according to claim 50and a pharmaceutically acceptable carrier.
 53. A pharmaceuticalcomposition comprising a compound according to claim 50 and apharmaceutically acceptable carrier.
 54. A pharmaceutical compositioncomprising a mixture of compounds of Formula II′ and Formula II″

or a pharmaceutically acceptable salt thereof.
 55. The pharmaceuticalcomposition according to claim 54, wherein the compound of Formula II′and the compound of Formula II″ are present in a molar ration of aboutat a ratio of about 1:1.
 56. The pharmaceutical composition according toclaim 54, wherein the compound of Formula II′ is present in an amount ofat least about 75 mol %.
 57. The pharmaceutical composition according toclaim 54, wherein the compound of Formula II′ is present in amount of atleast about 90 mol %.
 58. A pharmaceutical composition comprising acompound of the structure:

or a pharmaceutically acceptable salt or solvate thereof, or adeuterated form thereof, and a pharmaceutically acceptable carrier. 59.The composition according to claim 58, wherein the compound of FormulaII is in free base form.
 60. A method of delivering an IDO inhibitor ortreating cancer in a subject comprising delivering to a subject acomposition according to claim 58.